Long acting beta-2-agonists and their use as medicaments

ABSTRACT

A compound of formula 1′″ 
                         
wherein:
     V is —CH 2 —, —NH—, or —O—;   R a  and R b  are each independently hydrogen, C 1-4 -alkyl, or halogen-C 1-4 -alkyl, or   R a  and R b  together are a C 2-5 -alkylene bridge wherein one or more hydrogen atoms are optionally replaced by halogen;   R 1  and R 1′  are each independently hydrogen, C 1-6 -alkyl, C 3-6 -cycloalkyl, halogen-C 1-6 -alkyl, halogen-C 3-6 -cycloalkyl, or C 1-6 -alkylene-C 3-6 -cycloalkyl, or   R 1  and R 1′  together are a C 2-5 -alkylene bridge wherein one or more hydrogen atoms are optionally replaced by halogen;   R 2 , R 2′ , R 2″ , and R 2′″  are each independently hydrogen, C 1-6 -alkyl, halogen-C 1-6 -alkylene, OH, HO—C 1-6 -alkylene, —O—C 1-6 -alkyl, C 6-10 -aryl, C 6-10 -aryl-C 1-4 -alkylene, C 6-10 -aryl-C 1-6 -alkylene-O, COOH, COOC 1-6 -alkyl, O—C 1-6 -alkylene-COOH, O—C 1-6 -alkylene-COOC 1-6 -alkyl, NHSO 2 —C 1-6 -alkyl, CN, NH 2 , NH—C 1-6 -alkyl, N(C 1-6 -alkyl) 2 , NO 2 , S—C 1-6 -alkyl, SO 2 —C 1-6 -alkyl, SO—C 1-6 -alkyl, O(CO)C 1-6 -alkyl, COC 1-6 -alkyl, NHCOC 1-6 -alkyl, or halogen; and
 
n is 0, 1, or 2,
 
or an optical isomer thereof, or a corresponding acid addition salt thereof with a pharmacologically acceptable acid, and the use thereof as pharmaceutical compositions, particularly for the treatment of inflammatory and obstructive respiratory complaints.

RELATED APPLICATIONS

This application is a continuation of U.S. Ser. No. 11/600,417, filedNov. 15, 2006, now U.S. Pat. No. 7,375,104, which is a continuation ofU.S. Ser. No. 11/029,451, filed Jan. 5, 2005, now U.S. Pat. No.7,160,882, which claimed benefit of U.S. Provisional Application Ser.No. 60/557,081, filed on Mar. 26, 2004, and claims priority to GermanApplication 10 2004 003 428, filed on Jan. 23, 2004, each of which isincorporated herein in its entirety.

FIELD OF THE INVENTION

The present invention relates to compounds of formula 1

wherein the groups X, R^(a), R^(b), R¹, R^(1′), R², R^(2′), R^(2″),R^(2′″), V, and n may have the meanings given in the claims and in thespecification, processes for preparing them and their use aspharmaceutical compositions, particularly for the treatment ofinflammatory and obstructive respiratory complaints.

BACKGROUND TO THE INVENTION

Betamimetics (β-adrenergic substances) are known from the prior art. Inthis respect reference is made, for example, to the disclosure of EP 43940 or WO 01/83462, which propose betamimetics for the treatment of awide range of diseases.

For the drug treatment of diseases it is often desirable to preparemedicaments with a longer duration of activity. As a rule, this ensuresthat the concentration of the active substance in the body needed toachieve the therapeutic effect is guaranteed for a longer period withoutthe need to re-administer the drug at frequent intervals. Moreover,giving an active substance at longer time intervals contributes to thewellbeing of the patient to a high degree.

It is particularly desirable to prepare a pharmaceutical compositionwhich can be used therapeutically by administration once a day (singledose). The use of a drug once a day has the advantage that the patientcan become accustomed relatively quickly to regularly taking the drug atcertain times of the day.

The aim of the present invention is therefore to provide betamimeticswhich are characterized by a longer duration of activity and can thus beused to prepare pharmaceutical compositions with a longer duration ofactivity. A particular aim of the invention is to prepare betamimeticswhich, by virtue of their long-lasting effect, can be used to prepare adrug for administration once a day. A further objective of the inventionis to prepare new betamimetics which, by virtue of their long-lastingeffect, can be used to prepare a drug for administration once a day forthe treatment of inflammatory or obstructive respiratory complaints.

In addition to the above objectives, the present invention also sets outto provide betamimetics which are not only exceptionally potent but arealso characterized by a high degree of selectivity with respect to theβ₂-adrenoreceptor.

DETAILED DESCRIPTION OF THE INVENTION

Surprisingly it has been found that the abovementioned objectives areachieved by compounds of general formula 1.

Accordingly, the present invention relates to compounds of generalformula 1

wherein:

-   X denotes a group —O—, —NH—, —CH₂—O—, —CHMe-O—, —C(Me)₂-O—,    —CH₂—NH—, —CHMe-NH—, —C(Me)₂-NH—, —CH═CH—, or —CH₂—CH₂—;-   V denotes a double-bonded group selected from among CH₂, NH, and O,    preferably CH₂ and O, particularly preferably O;-   R^(a) and R^(b), which may be identical or different, denote a group    selected from among hydrogen, C₁₋₄-alkyl, and halogen-C₁₋₄-alkyl, or-   R^(a) and R^(b) together denote a C₂₋₅-alkylene-bridge, wherein one    or more hydrogen atoms may optionally be replaced by halogen;-   R¹ and R^(1′), which may be identical or different, denote a group    selected from among hydrogen, C₁₋₆-alkyl, C₃₋₆-cycloalkyl,    halogen-C₁₋₆-alkyl, halogen-C₃₋₆-cycloalkyl, or    C₁₋₆-alkylene-C₃₋₆-cycloalkyl, or-   R¹ and R^(1′) together denote a C₂₋₅-alkylene-bridge wherein one or    more hydrogen atoms may optionally be replaced by halogen;-   R², R^(2′), R^(2″), and R^(2′″), which may be identical or    different, denote a group selected from among hydrogen, C₁₋₁₆-alkyl,    halogen-C₁₋₆-alkylene, OH, HO—C₁₋₆-alkylene, —O—C₁₋₆-alkyl,    C₆₋₁₀-aryl, C₆₋₁₀-aryl-C₁₋₄-alkylene, C₆₋₁₀-aryl-C₁₋₆-alkylene-O,    COOH, COOC₁₋₆-alkyl, O—C₁₋₆-alkylene-COOH,    O—C₁₋₆-alkylene-COOC₁₋₆-alkyl, NHSO₂—C₁₋₆-alkyl, CN, NH₂,    NH—C₁₋₆-alkyl, N(C₁₋₆-alkyl)₂, NO₂, S—C₁₋₆-alkyl, SO₂—C₁₋₆-alkyl,    SO—C₁₋₆-alkyl, O(CO)C₁₋₆-alkyl, COC₁₋₆-alkyl, NHCOC₁₋₆-alkyl, or    halogen; and-   n denotes 0, 1, or 2, preferably 1,    optionally in the form of the individual optical isomers, mixtures    of the individual enantiomers or racemates, in the form of the free    bases or the corresponding acid addition salts with    pharmacologically acceptable acids.

Preferred are the compounds of formula 1 wherein:

-   X denotes —O—, —CH₂—O—, —C(Me)₂-O—, or —CH═CH—;-   V denotes a double-bonded group selected from the group consisting    of —CH₂—, —NH—, and —O—, preferably —CH₂— and —O—, particularly    preferably —O—;-   R^(a) and R^(b), which may be identical or different, denote a group    selected from among hydrogen, C₁₋₄-alkyl, and fluoro-C₁₋₄-alkyl, or-   R^(a) and R^(b) together denote a group selected from —CH₂—CH₂,    —CH₂—CH₂—CH₂—CH₂—, and —CH₂—CH₂—CH₂—CH₂—CH₂, wherein one or more    hydrogen atoms may optionally be replaced by fluorine or chlorine,    preferably fluorine;-   R¹ and R^(1′), which may be identical or different, denote a group    selected from among hydrogen, C₁₋₆-alkyl, C₃₋₆-cycloalkyl,    halogen-C₁₋₆-alkyl, or C₁₋₆-alkylene-C₃₋₆-cycloalkyl, or-   R¹ and R^(1′) together denote a group selected from —CH₂—CH₂,    —CH₂—CH₂—CH₂—CH₂— and —CH₂—CH₂—CH₂—CH₂—CH₂, wherein one or more    hydrogen atoms may optionally be replaced by fluorine or chlorine,    preferably fluorine;-   R², R^(2′), R^(2″), and R^(2′″), which may be identical or    different, denote a group selected from among hydrogen, C₁₋₄-alkyl,    CF₃, CHF₂, CH₂F, OH, —O—C₁₋₄-alkyl, phenyl, phenylethyl, benzyl,    phenyloxy, benzyloxy, COOH, COOC₁₋₄-alkyl, OCH₂COOH,    OCH₂COOC₁₋₄-alkyl, NHSO₂—C₁₋₄-alkyl, fluorine, chlorine, or bromine;-   n denotes 0, 1, or 2, preferably 1; and    optionally in the form of the individual optical isomers, mixtures    of the individual enantiomers or racemates, in the form of the free    bases or the corresponding acid addition salts with    pharmacologically acceptable acids.

Particularly preferred are the compounds of formula 1 wherein:

-   X denotes —O—, —CH₂—O—, —C(Me)₂-O—, or —CH═CH—;-   V denotes a double-bonded group selected from among —CH₂— and —O—,    preferably —O—;-   R^(a) and R^(b), which may be identical or different, denote a group    selected from among hydrogen, methyl, ethyl, and CF₃, preferably    hydrogen, methyl, or ethyl, or-   R^(a) and R^(b) together denote a group selected from —CH₂—CH₂— and    —CH₂—CH₂—CH₂—CH₂, preferably —CH₂—CH₂—;-   R¹ and R^(1′), which may be identical or different, denote a group    selected from among hydrogen, methyl, ethyl, propyl, cyclopropyl or    methylcyclopropyl, or-   R¹ and R^(1′) together denote —CH₂—CH₂—CH₂—CH₂— or    —CH₂—CH₂—CH₂—CH₂—CH₂—;-   R², R^(2′), R^(2″), and R^(2′″), which may be identical or    different, denote a group selected from among hydrogen, methyl,    ethyl, propyl, CF₃, CHF₂, CH₂F, OH, methyloxy, ethyloxy, propyloxy,    COOH, COOCH₃, COOCH₂CH₃, OCH₂COOH, OCH₂COOCH₃, NHSO₂—CH₃, fluorine,    chlorine, or bromine; and-   n denotes 0, 1, or 2, preferably 1,    optionally in the form of the individual optical isomers, mixtures    of the individual enantiomers or racemates, in the form of the free    bases or the corresponding acid addition salts with    pharmacologically acceptable acids.

Of particular importance according to the invention are the compounds offormula 1 wherein R^(a) and R^(b) both represent methyl and wherein thegroups X, R¹, R^(1′), R², R^(2′), R^(2″), R^(2′″), V, and n may have theabovementioned meanings. These preferred compounds may be represented bythe following general formula 1.1

wherein the groups X, R¹, R^(1′), R², R^(2′), R^(2″), R^(2′″), V, and nmay have the abovementioned meanings.

Of particular importance according to the invention are the compounds offormula 1 wherein X corresponds to the group —CH₂—O—. These compoundsmay be represented by the formula 1′

wherein the groups R^(a), R^(b), R¹, R^(1′), R², R^(2′), R^(2″),R^(2′″), and V are as hereinbefore defined.

Preferred compounds are those of formula 1′, wherein R^(a) and R^(b) mayhave the abovementioned meanings and wherein:

-   V denotes a double-bonded group selected from the group consisting    of —CH₂— and —O—, preferably —O—;-   R¹ and R^(1′), which may be identical or different, denote a group    selected from among hydrogen, methyl, ethyl, propyl, or cyclopropyl,    or-   R¹ and R^(1′) together denote —CH₂—CH₂—CH₂—CH₂— or    —CH₂—CH₂—CH₂—CH₂—CH₂—;-   R² and R^(2′″) denote hydrogen;-   R^(2′) and R^(2″), which may be identical or different, denote a    group selected from among hydrogen, methyl, CF₃, OH, methyloxy,    benzyloxy, COOH, COOCH₃, or fluorine; and-   n denotes 0, 1 or 2, preferably 1,    optionally in the form of the individual optical isomers, mixtures    of the individual enantiomers or racemates, in the form of the free    bases or the corresponding acid addition salts with    pharmacologically acceptable acids.

Preferred compounds of formula 1′ according to the invention are thosewherein R^(a) and R^(b) may have the abovementioned meanings andwherein:

-   V denotes a double-bonded group selected from among —CH₂— and —O—,    preferably —O—;-   R¹ and R^(1′), which may be identical or different, denote hydrogen,    methyl, ethyl, propyl, or cyclopropyl, or-   R¹ and R^(1′) together denote —CH₂—CH₂—CH₂—CH₂—CH₂—;-   R² and R^(2′″) denote hydrogen;-   R^(2′) and R^(2″), which may be identical or different, denote a    group selected from among hydrogen, methyl, CF₃, OH, methyloxy,    benzyloxy, or fluorine; and-   n denotes 0, 1, or 2, preferably 1,    optionally in the form of the individual optical isomers, mixtures    of the individual enantiomers or racemates, in the form of the free    bases or the corresponding acid addition salts with    pharmacologically acceptable acids.

Of equal importance according to the invention are the compounds offormula 1′, wherein R^(a) and R^(b) may have the abovementioned meaningsand wherein:

-   V denotes the double-bonded group O;-   R¹ and R^(1′), which may be identical or different, preferably    identical, denote hydrogen, methyl, ethyl, or propyl;-   R², R^(2″) and R^(2″) denote hydrogen;-   R^(2′) denotes hydrogen, OH, methyloxy, or benzyloxy; and-   n denotes 0, 1, or 2, preferably 1,    optionally in the form of the individual optical isomers, mixtures    of the individual enantiomers or racemates, in the form of the free    bases or the corresponding acid addition salts with    pharmacologically acceptable acids.

Also of exceptional importance according to the invention are thecompounds of formula 1′ wherein R^(a) and R^(b) may have theabovementioned meanings and wherein:

-   V denotes the double-bonded group —O—;-   R¹ and R^(1′) in each case simultaneously denote hydrogen, methyl,    ethyl, or propyl;-   R², R^(2″), and R^(2′″) denote hydrogen;-   R^(2′) denotes hydrogen, OH, or methyloxy; and-   n denotes 0, 1, or 2, preferably 1,    optionally in the form of the individual optical isomers, mixtures    of the individual enantiomers or racemates, in the form of the free    bases or the corresponding acid addition salts with    pharmacologically acceptable acids.

Also of particular importance according to the invention are thosecompounds of formula 1′ wherein R^(a) and R^(b) both represent methyl.These compounds may be represented by formula 1.1′

wherein the groups R¹, R^(1′), R², R^(2′), R^(2″), R^(2′″), and V mayhave the abovementioned meanings.

Preferred compounds of formula 1 are those wherein X corresponds to thegroup —O—. These compounds may be represented by the formula 1″

wherein the groups R^(a), R^(b), R¹, R^(1′), R², R^(2′), R^(2″),R^(2′″), and V have the abovementioned meanings.

Particularly preferred are compounds of formula 1″, wherein R^(a) andR^(b) may have the abovementioned meanings and wherein:

-   V denotes a double-bonded group selected from among CH₂ and O,    preferably O;-   R¹ and R^(1′), which may be identical or different, denote a group    selected from among hydrogen, methyl, ethyl, propyl, and    cyclopropyl, or-   R¹ and R^(1′) together denote —CH₂—CH₂—CH₂—CH₂— or    —CH₂—CH₂—CH₂—CH₂—CH₂—;-   R² and R^(2′″) denote hydrogen;-   R^(2′) and R^(2″), which may be identical or different, denote a    group selected from among hydrogen, methyl, CF₃, OH, methyloxy,    benzyloxy, COOH, COOCH₃, or fluorine;-   n denotes 0, 1, or 2, preferably 1,    optionally in the form of the individual optical isomers, mixtures    of the individual enantiomers or racemates, in the form of the free    bases or the corresponding acid addition salts with    pharmacologically acceptable acids.

Also particularly preferred are compounds of formula 1″, wherein R^(a)and R^(b) may have the abovementioned meanings and wherein:

-   V denotes a double-bonded group selected from among —CH₂— and —O—,    preferably —O—;-   R¹ and R^(1′), which may be identical or different, denote hydrogen,    methyl, ethyl, or propyl, or-   R¹ and R^(1′) together denote —CH₂—CH₂—CH₂—CH₂—CH₂—;-   R² and R^(2′″) denote hydrogen;-   R^(2′) and R^(2″), which may be identical or different, denote a    group selected from among hydrogen, methyl, CF₃, OH, methyloxy,    benzyloxy, or fluorine; and-   n denotes 0, 1, or 2, preferably 1,    optionally in the form of the individual optical isomers, mixtures    of the individual enantiomers or racemates, in the form of the free    bases or the corresponding acid addition salts with    pharmacologically acceptable acids.

Also of equal importance according to the invention are the compounds offormula 1″, wherein R^(a) and R^(b) may have the abovementioned meaningsand wherein:

-   V denotes the double-bonded group O;-   R¹ and R^(1′), which may be identical or different, preferably    identical, denote hydrogen, methyl, or ethyl;-   R², R^(2″), and R^(2″) denote hydrogen;-   R^(2′) denotes hydrogen, OH, methyloxy, or benzyloxy; and-   n denotes 0, 1, or 2, preferably 1,    optionally in the form of the individual optical isomers, mixtures    of the individual enantiomers or racemates, in the form of the free    bases or the corresponding acid addition salts with    pharmacologically acceptable acids.

Also of particular importance according to the invention are thosecompounds of formula 1″ wherein R^(a) and R^(b) both represent methyl.These compounds may be represented by the formula 1.1″

wherein the groups R¹, R^(1′), R², R^(2′), R^(″), R^(2′″), and V mayhave the abovementioned meanings.

Also of particular importance according to the invention are compoundsof formula 1 wherein X corresponds to the group —CH═CH—. These compoundsmay be represented by the formula 1′″

wherein the groups R^(a), R^(b), R¹, R^(1′), R², R^(2′), R^(2″),R^(2′″), and V are as hereinbefore defined.

Preferred are compounds of formula 1′″ wherein R^(a) and R^(b) may havethe abovementioned meanings and wherein:

-   V denotes a double-bonded group selected from among —CH₂— and —O—,    preferably —O—;-   R¹ and R^(1′), which may be identical or different, denote a group    selected from among hydrogen, methyl, ethyl, propyl, and    cyclopropyl, preferably methyl or ethyl, or-   R¹ and R^(1′) together denote —CH₂—CH₂, —CH₂—CH₂—CH₂—CH₂—, or    —CH₂—CH₂—CH₂—CH₂—CH₂—;-   R² and R^(2′″) denote hydrogen;-   R^(2′) and R^(2″), which may be identical or different, denote a    group selected from among hydrogen, methyl, CF₃, OH, methyloxy,    benzyloxy, COOH, COOCH₃, or fluorine; and-   n denotes 0, 1, or 2, preferably 1,    optionally in the form of the individual optical isomers, mixtures    of the individual enantiomers or racemates, in the form of the free    bases or the corresponding acid addition salts with    pharmacologically acceptable acids.

Particularly preferred are compounds of formula 1′″, wherein R^(a) andR^(b) may have the abovementioned meanings and wherein:

-   V denotes a double-bonded group selected from the group consisting    from —CH₂— and —O—, preferably —O—;-   R¹ and R^(1′), which may be identical or different, denote hydrogen    methyl, ethyl, or propyl, or-   R¹ and R^(1′) together denote —CH₂—CH₂, —CH₂—CH₂—CH₂—CH₂—, or    —CH₂—CH₂—CH₂—CH₂—CH₂—;-   R² and R^(2′″) denote hydrogen;-   R^(2′) and R^(2″), which may be identical or different denote a    group selected from among hydrogen, methyl, CF₃, OH, methyloxy,    benzyloxy, or fluorine; and-   n denotes 0, 1, or 2, preferably 1,    optionally in the form of the individual optical isomers, mixtures    of the individual enantiomers or racemates, in the form of the free    bases or the corresponding acid addition salts with    pharmacologically acceptable acids.

Also particularly preferred are compounds of formula 1′″ wherein R^(a)and R^(b) may have the abovementioned meanings and wherein:

-   V denotes the double-bonded group —O—;-   R¹ and R^(1′), which may be identical or different, preferably    identical, denote hydrogen, methyl, ethyl, or propyl;-   R², R^(2″), and R^(2″) denote hydrogen;-   R^(2′) denotes hydrogen, OH, methyloxy, or benzyloxy; and-   n denotes 0, 1, or 2, preferably 1,    optionally in the form of the individual optical isomers, mixtures    of the individual enantiomers or racemates, in the form of the free    bases or the corresponding acid addition salts with    pharmacologically acceptable acids.

Also of exceptional importance according to the invention are thecompounds of formula 1′″, wherein R^(a) and R^(b) may have theabovementioned meanings and wherein:

-   V denotes the double-bonded group —O—;-   R¹ and R^(1′) in each case simultaneously denote hydrogen, methyl,    ethyl, or propyl;-   R², R^(2″), and R^(2′″) denote hydrogen;-   R^(2′) denotes hydrogen, OH, or methyloxy; and-   n denotes 0, 1, or 2, preferably 1,    optionally in the form of the individual optical isomers, mixtures    of the individual enantiomers or racemates, in the form of the free    bases or the corresponding acid addition salts with    pharmacologically acceptable acids.

Also of particular importance according to the invention are thosecompounds of formula 1′″ wherein R^(a) and R^(b) both represent methyl.These compounds may be represented by the formula 1.1′″

wherein the groups R¹, R^(1′), R², R^(2′), R^(2″), R^(2′″), and V mayhave the abovementioned meanings.

Also of particular importance according to the invention are compoundsof formula 1 wherein X denotes the group —CMe₂-O—. These compounds maybe represented by the formula 1″″

wherein the groups R^(a), R^(b), R¹, R^(1′), R², R^(2′), R^(2″),R^(2′″), and V are as hereinbefore defined.

Preferred are compounds of formula 1′″ wherein R^(a) and R^(b) may havethe abovementioned meanings and wherein:

-   V denotes a double-bonded group selected from among —CH₂— and —O—,    preferably —O—;-   R¹ and R^(1′), which may be identical or different, denote a group    selected from among hydrogen, methyl, ethyl, propyl, and    cyclopropyl, or-   R¹ and R^(1′) together denote —CH₂—CH₂—CH₂—CH₂— or    —CH₂—CH₂—CH₂—CH₂—CH₂—;-   R² and R^(2′″) denote hydrogen;-   R^(2′) and R^(2″), which may be identical or different, denote a    group selected from among hydrogen, methyl, CF₃, OH, methyloxy,    benzyloxy, COOH, COOCH₃, or fluorine; and-   n denotes 0, 1, or 2, preferably 1,    optionally in the form of the individual optical isomers, mixtures    of the individual enantiomers or racemates, in the form of the free    bases or the corresponding acid addition salts with    pharmacologically acceptable acids.

Particularly preferred are compounds of formula 1″″ wherein R^(a) andR^(b) may have the abovementioned meanings and wherein:

-   V denotes a double-bonded group selected from among CH₂ and O,    preferably O;-   R¹ and R^(1′), which may be identical or different, denote hydrogen,    methyl, ethyl, or propyl, or-   R¹ and R^(1′) together denote —CH₂—CH₂—CH₂—CH₂—CH₂—;-   R² and R^(2′″) denote hydrogen;-   R^(2′) and R^(2″), which may be identical or different, denote a    group selected from among hydrogen, methyl, CF₃, OH, methyloxy,    benzyloxy, or fluorine;-   n denotes 0, 1, or 2, preferably 1,    optionally in the form of the individual optical isomers, mixtures    of the individual enantiomers or racemates, in the form of the free    bases or the corresponding acid addition salts with    pharmacologically acceptable acids.

Also particularly preferred are the compounds of formula 1″″, whereinR^(a) and R^(b) may have the abovementioned meanings and wherein:

-   V denotes the double-bonded group —O—;-   R¹ and R^(1′), which may be identical or different, preferably    identical, denote hydrogen, methyl, ethyl, or propyl;-   R², R^(2″), and R^(2″) denote hydrogen;-   R^(2′) denotes hydrogen, OH, methyloxy, or benzyloxy; and-   n denotes 0, 1, or 2, preferably 1,    optionally in the form of the individual optical isomers, mixtures    of the individual enantiomers or racemates, in the form of the free    bases or the corresponding acid addition salts with    pharmacologically acceptable acids.

Also of exceptional importance according to the invention are thecompounds of formula 1″″, wherein R^(a) and R^(b) may have theabovementioned meanings and wherein:

-   V denotes the double-bonded group —O—;-   R¹ and R^(1′) in each case simultaneously denote hydrogen, methyl,    ethyl, or propyl;-   R², R^(2″), and R^(2′″) denote hydrogen;-   R^(2′) denotes hydrogen, OH, or methyloxy,-   n denotes 0, 1, or 2, preferably 1;    optionally in the form of the individual optical isomers, mixtures    of the individual enantiomers or racemates, in the form of the free    bases or the corresponding acid addition salts with    pharmacologically acceptable acids.

Also of particular importance according to the invention are thosecompounds of formula 1″″ wherein R^(a) and R^(b) both represent methyl.These compounds may be represented by the formula 1.1″″

wherein the groups R¹, R^(1′), R², R^(2′), R^(2″), R^(2′″), and V mayhave the abovementioned meanings.

Also of outstanding importance according to the invention are thecompounds of formula 1 wherein:

-   R¹ and R^(1′) in each case simultaneously denote hydrogen, methyl,    or ethyl, preferably methyl or ethyl, particularly preferably ethyl;    and the groups X, R², R^(2′), R^(2″), R^(2′″), V, and n may have one    of the abovementioned meanings, optionally in the form of the    individual optical isomers, mixtures of the individual enantiomers    or racemates, in the form of the free bases or the corresponding    acid addition salts with pharmacologically acceptable acids.

Also of exceptional importance according to the invention are thecompounds of formula 1, wherein n is 1 and the groups X, R¹, R^(1′), R²,R^(2′), R^(2″), R^(2′″), and V may have one of the abovementionedmeanings, optionally in the form of the individual optical isomers,mixtures of the individual enantiomers or racemates, in the form of thefree bases or the corresponding acid addition salts withpharmacologically acceptable acids.

Particularly preferred compounds of general formula 1 are selected fromamong:

-   1-{3-[2-hydroxy-2-(6-hydroxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)ethylamino]-3-methylbutyl}-6-methoxy-4,4-dimethyl-1,4-dihydrobenzo[d][1,3]oxazin-2-one;-   6-hydroxy-1-{3-[2-hydroxy-2-(6-hydroxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)ethylamino]-3-methylbutyl}-4,4-dimethyl-1,4-dihydrobenzo[d][1,3]oxazin-2-one;-   4,4-diethyl-1-{3-[2-hydroxy-2-(6-hydroxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)ethylamino]-3-methylbutyl}-1,4-dihydrobenzo[d][1,3]oxazin-2-one;-   6-hydroxy-8-{1-hydroxy-2-[3-(3-hydroxy-4,4-dimethyl-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl)-1,1-dimethylpropylamino]ethyl}-4H-benzo[1,4]oxazin-3-one;-   1-{3-[2-hydroxy-2-(6-hydroxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)ethylamino]-3-methylbutyl}-1,4-dihydrobenzo[1,3]oxazin-2-one;-   4-ethyl-1-{3-[2-hydroxy-2-(6-hydroxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)ethylamino]-3-methylbutyl}-1,4-dihydrobenzo[1,3]oxazin-2-one;-   8-{2-[1,1-dimethyl-3-(2-oxo-3,4-dihydro-2H-quinolin-1-yl)propylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one;-   4,4-diethyl-1-{3-[2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]-3-methylbutyl}-1,4-dihydrobenzo[1,3]oxazin-2-one;-   4,4-diethyl-1-{3-[2-hydroxy-2-(6-hydroxy-2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)ethylamino]-3-methylbutyl}-1,4-dihydrobenzo[d][1,3]oxazin-2-one;-   4,4-diethyl-1-{3-[2-hydroxy-2-(6-hydroxy-2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)ethylamino]-3-methylbutyl}-1,4-dihydrobenzo[d][1,3]oxazin-2-one;-   4,4-diethyl-1-{3-[2-hydroxy-2-(7-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]-3-methylbutyl}-1,4-dihydrobenzo[d][1,3]oxazin-2-one;-   1-{3-[2-hydroxy-2-(6-hydroxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)ethylamino]-3-methylbutyl}-4,4-dipropyl-1,4-dihydrobenzo[d][1,3]oxazin-2-one;-   1-{3-[2-hydroxy-2-(5-hydroxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)ethylamino]-3-methylbutyl}-4,4-dipropyl-1,4-dihydrobenzo[d][1,3]oxazin-2-one;-   4,4-diethyl-7-fluoro-1-{3-[2-hydroxy-2-(6-hydroxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)ethylamino]-3-methylbutyl}-1,4-dihydrobenzo[d][1,3]oxazin-2-one;-   4,4-diethyl-1-{3-[2-hydroxy-2-(5-hydroxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)ethylamino]-3-methylbutyl}-8-methoxy-1,4-dihydrobenzo[d][1,3]oxazin-2-one;-   1-(2-{1-[2-hydroxy-2-(5-hydroxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)ethylamino]cyclopropyl}ethyl)-4,4-dimethyl-1,4-dihydrobenzo[d][1,3]oxazin-2-one;-   1-(2-{1-[2-hydroxy-2-(6-hydroxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)ethylamino]cyclopropyl}ethyl)-4,4-dimethyl-1,4-dihydrobenzo[d][1,3]oxazin-2-one;-   1-{3-[2-hydroxy-2-(6-hydroxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)ethylamino]-3-methylbutyl}spiro(cyclohexane-1,4′-2H-3′,1′-benzoxazin)-2′-one;-   1-{3-[2-hydroxy-2-(5-hydroxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)ethylamino]-3-methylbutyl}spiro(cyclohexane-1,4′-2H-3′,1′-benzoxazin)-2′-one;-   4,4-dimethyl-1-{3-[2-hydroxy-2-(6-hydroxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)ethylamino]propyl}-1,4-dihydrobenzo[d][1,3]oxazin-2-one;    and-   4,4-dimethyl-1-{3-[2-hydroxy-2-(5-hydroxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)ethylamino]propyl}-1,4-dihydrobenzo[d][1,3]oxazin-2-one,    optionally in the form of the individual optical isomers, mixtures    of the individual enantiomers or racemates, in the form of the free    bases or the corresponding acid addition salts with    pharmacologically acceptable acids.

The OH group may be configured in three different positions in thecompounds of formula 1 defined hereinbefore. The preferred isomers maybe represented by the following general formulae 1a and 1b

wherein the groups X, R^(a), R^(b), R¹, R^(1′), R², R^(2′), R^(2″),R^(2′″), V, and n may have the abovementioned meanings.

Particularly preferred compounds are particularly also those of generalformula 1.1′-b

wherein the groups R¹, R^(1′), R², R^(2′), R^(2″), R^(2′″), and V mayhave the abovementioned meanings.

Particularly preferred compounds are particularly also those of generalformula 1.1″-b

wherein the groups R¹, R^(1′), R², R^(2′), R^(2″), R^(2′″), and V mayhave the abovementioned meanings.

Particularly preferred compounds are particularly also those of generalformula 1.1′″-a

wherein the groups R¹, R^(1′), R², R^(2′), R^(2″), R^(2′″), and V mayhave the abovementioned meanings.

Particularly preferred compounds are particularly also those of generalformula 1.1″″-b

wherein the groups R¹, R^(1′), R², R^(2′), R^(2″), R^(2′″), and V mayhave the abovementioned meanings.

The compounds of formula 1 may optionally be used in the form of theindividual optical isomers, mixtures of the individual enantiomers orracemates. They are particularly preferably used in the form of theenantiomerically pure compounds, while the compounds of formula 1wherein the asymmetric carbon center “—CH(OH)—” benzylic to the phenylring is in the R configuration [sic]. The particularly preferredR-enantiomers of the compounds of general formula 1 may be representedby general formula R-1

wherein the groups X, R^(a), R^(b), R¹, R^(1′), R², R^(2′), R^(2″),R^(2′″), V, and n may have the abovementioned meanings.

By acid addition salts with pharmacologically acceptable acids aremeant, for example, the salts selected from among the hydrochloride,hydrobromide, hydroiodide, hydrosulfate, hydrophosphate,hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate,hydrobenzoate, hydrocitrate, hydrofumarate, hydrotartrate, hydrooxalate,hydrosuccinate, hydrobenzoate, and hydro-p-toluenesulfonate, preferablythe hydrochloride, hydrobromide, hydrosulfate, hydrophosphate,hydrofumarate, and hydromethanesulfonate.

Halogen within the scope of the present invention denotes fluorine,chlorine, bromine or iodine. Unless stated otherwise, fluorine andbromine are the preferred halogens, while fluorine is generallypreferred.

Unless otherwise stated, the alkyl groups (alkyl) are straight-chainedor branched alkyl groups having 1 to 6, preferably 1 to 4 carbon atoms.The following are mentioned by way of example: methyl, ethyl, propyl orbutyl. In some cases the abbreviations Me, Et, Prop or Bu are used todenote the groups methyl, ethyl, propyl or butyl. Unless otherwisestated, the definitions propyl and butyl include all the possibleisomeric forms of the groups in question. Thus, for example, propylincludes n-propyl and isopropyl, butyl includes isobutyl, sec-butyl andtert-butyl, etc.

Examples of alkylene groups (alkylene), unless otherwise stated, arebranched and unbranched alkylene groups with 1 to 6, preferably 1 to 4carbon atoms. The following are mentioned by way of example: methylene,ethylene, propylene or butylene. Unless stated otherwise, thedefinitions propylene and butylene include all the possible isomericforms of the groups in question.

Examples of cycloalkyl groups (cycloalkyl), unless otherwise stated, arecyclic alkyl groups with 3 to 6. The following are mentioned by way ofexample: cyclopropyl, cyclobutanyl, cyclopentyl or cyclohexyl.

Examples of alkyloxy groups (O-alkyl), unless otherwise stated, arebranched and unbranched alkyl groups with 1 to 6, preferably 1 to 4carbon atoms, linked via an oxygen atom. The following are mentioned byway of example: methyloxy, ethyloxy, propyloxy, or butyloxy. In somecases the abbreviations —OMe, —OEt, —Oprop, or —OBu are used to denotethe groups methyloxy, ethyloxy, propyloxy or butyloxy. Unless statedotherwise, the definitions propyloxy and butyloxy include all thepossible isomeric forms of the groups in question. Thus, for example,propyloxy includes n-propyloxy and isopropyloxy, butyloxy includesisobutyloxy, sec-butyloxy, and tert-butyloxy, etc. In some cases withinthe scope of the present invention the term alkoxy may be used insteadof the term alkyloxy. The groups methyloxy, ethyloxy, propyloxy, or alsobutyloxy may optionally also be referred to as methoxy, ethoxy, propoxy,or butoxy.

Examples of halogenoalkylene groups, unless otherwise stated, arebranched and unbranched alkyl groups with 1 to 6 carbon atoms, whereinone or more hydrogen atoms are replaced by halogen atoms, preferably byfluorine. The following are mentioned, for example: CHF₂, CF₃, CH₂CF₃,and CF₂CF₃.

Suitable aryl groups, unless otherwise stated, are aromatic ring systemswith 6 to 10 carbon atoms. Preferred aryl groups are phenyl andnaphthyl, while phenyl is particularly preferred according to theinvention.

The term arylalkylene groups, unless otherwise stated, refers to theabovementioned aryl groups which are linked via branched and unbranchedalkyl groups with 1 to 4 carbon atoms. Examples include benzyl,phenylethyl, naphthylmethyl, and naphthylethyl. The bridging alkylgroups are also referred to, within the scope of the present invention,as alkylene bridges.

The term aryloxy groups (O-aryl), unless otherwise stated, refers toaryl groups with 6 to 10 carbon atoms which are linked via an oxygenbridge. Preferred groups in this context include for example phenyloxyor naphthyloxy, which may optionally also be referred to as phenoxy ornaphthoxy within the scope of the present invention.

The term arylalkylenoxy groups (arylalkylene-O—), unless otherwisestated, refers to aryl groups which are linked via branched andunbranched alkyloxy groups with 1 to 4 carbon atoms. Examples includebenzyloxy, phenylethyloxy, naphthylmethyloxy, and naphthylethyloxy.

The compounds according to the invention may be prepared analogously tomethods already known in the art. Suitable methods of preparation areknown, for example, from EP 43 940 or from WO 01/83462, to whichreference is hereby made in its entirety.

The examples of synthesis described below serve to illustrate newcompounds according to the invention in more detail. However, they areintended only as examples of procedures to illustrate the inventionwithout restricting it to the subject matter described in anexemplifying capacity hereinafter.

EXAMPLE 11-{3-[2-hydroxy-2-(6-hydroxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)ethylamino]-3-methylbutyl}-6-methoxy-4,4-dimethyl-1,4-dihydrobenzo[d][1,3]oxazin-2-one

a) ethyl (2-acetyl-4-methoxyphenyl)carbamate

65.1 g (0.6 mol) of ethyl chloroformate is added dropwise to a solutionof 82.5 g (0.5 mol) of 2-amino-5-methoxyacetophenone in 400 mL pyridinewhile cooling, so that the temperature does not exceed 10° C.-15° C.Then the reaction mixture is stirred for 2 hours at ambient (room)temperature and then poured onto ice. The precipitate formed is suctionfiltered, washed with water and recrystallized from isopropanol. Yield:102 g (86%); m.p.=97° C.-100° C.

b) 6-methoxy-4,4-dimethyl-1,4-dihydrobenzo[1,3]oxazin-2-one

47.4 g (0.2 mol) of ethyl (2-acetyl-4-methoxyphenyl)carbamate, dissolvedin 275 mL of THF, are added dropwise to a solution of 0.5 mol ofmethylmagnesium iodide in 200 mL of diethyl ether while cooling so thatthe temperature does not exceed 0° C. The mixture is stirred for 30minutes at ambient temperature and then for 2 hours at refluxtemperature. The reaction mixture is poured onto ice and combined withammonium chloride. After the organic phase has been separated off, it isrepeatedly extracted with ethyl acetate. The organic phases arecombined, washed with water, dried with sodium sulfate, and evaporateddown. The residue is dissolved in methanol and the solution isevaporated down and then combined with water. The precipitate formed isseparated off, washed with water and recrystallized from toluene. Yield:31.1 g (75%); m.p.=178° C.-180° C.

c)1-(3-amino-3-methylbutyl)-6-methoxy-4,4-dimethyl-1,4-dihydrobenzo[1,3]oxazin-2-one

A solution of 31 g (0.15 mol) of6-methoxy-4,4-dimethyl-1,4-dihydrobenzo[1,3]oxazin-2-one in 120 mL ofHMPT is added dropwise at 65° C.-70° C. to 7.2 g of sodium hydride(55%-60%) in 30 mL of HMPT. After the release of hydrogen has ended, themixture is stirred for another 20 minutes and then cooled to ambienttemperature. At this temperature, 37.7 g (0.18 mol) of(3-chloro-1,1-dimethylpropyl)benzylideneamine, dissolved in 40 mL HMPT,are added. After 3 hours stirring at 100° C., the reaction mixture ispoured onto ice poured and extracted with ethyl acetate. The organicphases are washed with water, dried with sodium sulfate, and evaporateddown. The residue is dissolved in 1 N hydrochloric acid with heating andafter cooling extracted with diethyl ether. The aqueous phase is madealkaline with sodium hydroxide solution and extracted with ethylacetate. Then the organic phase is dried with sodium sulfate and freedfrom solvent. The product is isolated from the residue in the form ofits hydrochloride, after dissolving in acetonitrile and adding etherealhydrochloric acid. Yield: 34.3 g (70%).

d)1-{3-[2-(6-benzyloxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-2-hydroxyethylamino]-3-methylbutyl}-6-methoxy-4,4-dimethyl-1,4-dihydrobenzo[1,3]oxazin-2-one

357 mg (1 mmol) of6-benzyloxy-8-(2-ethoxy-2-hydroxyacetyl)-4H-benzo[1,4]oxazin-3-one and292 mg (1 mmol) of1-(3-amino-3-methylbutyl)-6-methoxy-4,4-dimethyl-1,4-dihydrobenzo[1,3]oxazin-2-oneare suspended in 5 mL ethanol and heated to 70° C. The solution obtainedis stirred for one hour at 70° C. and then cooled to ambienttemperature. After the addition of 113 mg (3 mmol) of sodium borohydridethe mixture is stirred for 3 hours at ambient temperature, combined with0.7 mL saturated potassium carbonate solution and stirred for a further30 minutes. It is filtered through aluminum oxide (basic), washedrepeatedly with methylene chloride/methanol 15:1 and evaporated down.The crude product thus obtained is purified by chromatography (methylenechloride with methanol/ammonia gradient (9:1)). Beige solid. Yield: 340mg (58%); mass spectrometry: [M+H]⁺=590.

e)1-{3-[2-hydroxy-2-(6-hydroxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)ethylamino]-3-methylbutyl}-6-methoxy-4,4-dimethyl-1,4-dihydrobenzo[d][1,3]oxazin-2-one

340 mg (0.58 mmol) of1-{3-[2-(6-benzyloxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-2-hydroxyethylamino]-3-methylbutyl}-6-methoxy-4,4-dimethyl-1,4-dihydrobenzo[1,3]oxazin-2-oneis dissolved in 10 mL of methanol and hydrogenated with palladium oncharcoal as catalyst at 1 bar hydrogen pressure. Then the catalyst isfiltered off and the filtrate is evaporated down. Beige solid. Yield:273 mg (95%); mass spectrometry: [M+H]⁺=500; R_(f) value=0.33 (methylenechloride:methanol:ammonia=9:1:0.1).

EXAMPLE 26-hydroxy-1-{3-[2-hydroxy-2-(6-hydroxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)ethylamino]-3-methylbutyl}-4,4-dimethyl-1,4-dihydrobenzo[d][1,3]oxazin-2-one

a) 6-benzyloxy-4,4-dimethyl-1,4-dihydrobenzo[1,3]oxazin-2-one

Prepared analogously to the method described for Example 1b) from 15.7 g(50 mmol) of ethyl (2-acetyl-4-benzyloxyphenyl)carbamate and 125 mmol ofmethylmagnesium iodide. Yield: 10.8 g (76%); m.p.=134° C.

b)1-(3-amino-3-methylbutyl)-6-benzyloxy-4,4-dimethyl-1,4-dihydrobenzo[1,3]oxazin-2-one

Prepared analogously to the method described for Example 1c) from 10.5 g(37 mmol) of 6-benzyloxy-4,4-dimethyl-1,4-dihydrobenzo[1,3]oxazin-2-oneand 9.3 g (44 mmol) of (3-chloro-1,1-dimethylpropyl)benzylideneamine.Yield: 10.9 g (73%); m.p.=233° C. (hydrochloride).

c)6-hydroxy-1-{3-[2-hydroxy-2-(6-hydroxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)ethylamino]-3-methylbutyl}-4,4-dimethyl-1,4-dihydrobenzo[1,3]oxazin-2-one

The reaction of 357 mg (1 mmol) of6-benzyloxy-8-(2-ethoxy-2-hydroxyacetyl)-4H-benzo[1,4]oxazin-3-one and368 mg (1 mmol) of1-(3-amino-3-methylbutyl)-6-benzyloxy-4,4-dimethyl-1,4-dihydrobenzo[1,3]oxazin-2-oneanalogously to the methods described for Example 1 yields the compoundin the form of a beige solid. Yield 355 mg (73%); mass spectrometry:[M+H]⁺=486.

EXAMPLE 34,4-diethyl-1-{3-[2-hydroxy-2-(6-hydroxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)ethylamino]-3-methylbutyl}-1,4-dihydrobenzo[d][1,3]oxazin-2-one

a) 4,4-diethyl-1,4-dihydrobenzo[1,3]oxazin-2-one

Obtained from the reaction of 67 g (0.3 mol) of methyl2-ethoxycarbonylaminobenzoate and 1.14 mol ethylmagnesium iodideanalogously to the method described for Example 1b). Yield: 48.5 g(79%); m.p.=160° C.-162° C.

b)1-(3-amino-3-methylbutyl)-4,4-diethyl-1,4-dihydrobenzo[1,3]oxazin-2-one

Prepared from 47.5 g (0.23 mol) of4,4-diethyl-1,4-dihydrobenzo[1,3]oxazin-2-one and 57.5 g (0.27 mol) of(3-chloro-1,1-dimethylpropyl)benzylideneamine according to the methoddescribed for Example 1c). Yield: 38.1 g (50%); m.p.=208° C.-210° C.(hydrochloride).

c)4,4-diethyl-1-{3-[2-hydroxy-2-(6-hydroxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)ethylamino]-3-methylbutyl}-1,4-dihydrobenzo[d][1,3]oxazin-2-one

357 mg (1 mmol) of6-benzyloxy-8-(2-ethoxy-2-hydroxyacetyl)-4H-benzo[1,4]oxazin-3-one and290 mg (1 mmol) of1-(3-amino-3-methylbutyl)-4,4-diethyl-1,4-dihydrobenzo[1,3]oxazin-2-oneare reacted analogously to the methods described for Example 1. Aftersubsequent debenzylation, a beige solid is obtained. Yield: 367 mg(74%); mass spectrometry: [M+H]⁺=498.

EXAMPLE 41-{3-[2-hydroxy-2-(6-hydroxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)ethylamino]-3-methylbutyl}-4,4-dimethyl-1,4-dihydrobenzo[d][1,3]oxazin-2-one

a) 4,4-dimethyl-1,4-dihydrobenzo[1,3]oxazin-2-one

112 g (1.13 mol) of phosgene are piped into 500 mL of THF. Then asolution of 52 g (0.34 mol) of 2-(2-aminophenyl)propan-2-ol, preparedfrom 2-aminoacetophenone and methylmagnesium iodide, in 300 mL of THF isadded. The reaction mixture is left to stand overnight, evaporated down,and combined with 500 mL of pyridine. After the pyridine has beendistilled off, water is added and the mixture is extracted with diethylether. The organic phases are washed successively with 2 N hydrochloricacid, sodium hydroxide solution and water, dried with sodium sulfate,and evaporated down. The residue remaining (46 g) is further reacteddirectly without any more purification. M.p. (toluene/petroleumether)=109° C.-110° C.

b)1-(3-amino-3-methylbutyl)-4,4-dimethyl-1,4-dihydrobenzo[1,3]oxazin-2-one

Obtained from 43 g (0.24 mol) of4,4-dimethyl-1,4-dihydrobenzo[1,3]oxazin-2-one and 54 g (0.26 mol) of(3-chloro-1,1-dimethylpropyl)benzylideneamine analogously to the methoddescribed for Example 1c). Yield 41 g (57%); m.p. (afterrecrystallization from ethanol)=262° C. (hydrochloride).

c)1-{3-[2-hydroxy-2-(6-hydroxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)ethylamino]-3-methylbutyl}-4,4-dimethyl-1,4-dihydrobenzo[d][1,3]oxazin-2-one

357 mg (1 mmol) of6-benzyloxy-8-(2-ethoxy-2-hydroxyacetyl)-4H-benzo[1,4]oxazin-3-one and262 mg (1 mmol) of1-(3-amino-3-methylbutyl)-4,4-dimethyl-1,4-dihydrobenzo[1,3]oxazin-2-oneare reacted in the manner described for Example 1. After subsequenthydrogenation, a beige solid is isolated. Yield: 285 mg (61%); massspectrometry [M+H]⁺=470.

EXAMPLE 51-{3-[2-hydroxy-2-(6-hydroxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)ethylamino]-3-methylbutyl}-1,4-dihydrobenzo[1,3]oxazin-2-one

a) 1-(3-amino-3-methylbutyl)-1,4-dihydrobenzo[1,3]oxazin-2-one

2.70 g (18 mmol) of 1,4-dihydrobenzo[1,3]oxazin-2-one and 4.35 g (21mmol) of (3-chloro-1,1-dimethylpropyl)-(1-phenylmethylidene)amine arereacted in the manner described for Example 6a). For working up, thereaction mixture is poured onto ice water and extracted with ethylacetate. The organic phases are washed with water, dried with sodiumsulfate, and evaporated down. The residue is combined with 25 mL 2 Nhydrochloric acid and heated to 70° C. After cooling to ambienttemperature, the mixture is extracted with diethyl ether. The aqueousphase is evaporated down and combined with acetonitrile. The precipitateformed is suction filtered and washed with acetonitrile and diethylether. Yield: 2.65 g (54%, hydrochloride); melting range: 220° C.(decomposition).

b)1-{3-[2-(6-benzyloxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-2-hydroxyethylamino]-3-methylbutyl}-1,4-dihydrobenzo[1,3]oxazin-2-one

357 mg (1 mmol) of6-benzyloxy-8-(2-ethoxy-2-hydroxyacetyl)-4H-benzo[1,4]oxazin-3-one and234 mg (1 mmol) of1-(3-amino-3-methylbutyl)-1,4-dihydrobenzo[1,3]oxazin-2-one in 5 mL oftetrahydrofuran are stirred for 15 minutes at 60° C. The mixture iscooled to 0° C. and 1.5 mL of a 2 molar solution of lithium borohydridein tetrahydrofuran are added dropwise under an argon atmosphere. Themixture is stirred for 15 minutes at 0° C., combined with 10 mL ofdichloromethane and 3 mL of water, stirred for another hour, and thenfiltered through kieselguhr. The mixture is eluted with dichloromethaneand the solvents are distilled off. The residue is purified bypreparative HPLC (reverse phase, acetonitrile/water gradient with 0.1%trifluoroacetic acid). Yield: 196 mg (30%, trifluoroacetate); massspectroscopy: [M]⁺=532.

c)1-{3-[2-(6-benzyloxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-2-hydroxyethylamino]-3-methylbutyl}-1,4-dihydrobenzo[1,3]oxazin-2-one

196 mg (0.3 mmol) of1-{3-[2-(6-benzyloxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-2-hydroxyethylamino]-3-methylbutyl}-1,4-dihydrobenzo[1,3]oxazin-2-oneis dissolved in 5 ethanol and hydrogenated with palladium on charcoal(10%) as catalyst at 3 bar and ambient temperature. The catalyst isseparated off and the crude product is recrystallized fromacetonitrile/diethyl ether. Yield: 48 mg (29%, trifluoroethyl acetate);mass spectroscopy: [M+H]⁺=442.

EXAMPLE 64-ethyl-1-{3-[2-hydroxy-2-(6-hydroxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)ethylamino]-3-methylbutyl}-1,4-dihydrobenzo[1,3]oxazin-2-one

a) 1-(3-amino-3-methylbutyl)-4-ethyl-1,4-dihydrobenzo[1,4]oxazine

A solution of 17.7 g (0.10 mol) of4-ethyl-1,4-dihydrobenzo[1,3]oxazin-2-one in 85 mL of HMPT is combinedwith 4.8 g of sodium hydride (55-60%) and slowly heated to 60° C. Afterthe development of hydrogen has ended the mixture is stirred for another30 minutes at 80° C. and then cooled to ambient temperature. 25 g (0.12mol) of (3-chloro-1,1-dimethylpropyl)-(1-phenylmethylidene)amine,dissolved in 25 mL of HMPT, is added and the mixture is stirred forthree hours at 100° C. The reaction mixture is cooled, poured onto icewater, and extracted with ethyl acetate. The combined organic phases arewashed with water, dried with sodium sulfate, and evaporated down. Theresidue is heated to 60° C. together with 240 mL 1N hydrochloric acidand after cooling extracted with diethyl ether. The aqueous phase ismade alkaline with concentrated sodium hydroxide solution and extractedwith ethyl acetate. The combined organic phases are dried with sodiumsulfate and evaporated down. The residue is dissolved in ethyl acetatewith heating, combined with an equimolar amount of maleic acid, andslowly cooled. The precipitate formed is suction filtered, washed withethyl acetate and dried. Yield: 26.1 g (69%, maleate); melting range:134° C.

b)1-{3-[2-(6-benzyloxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-2-hydroxyethylamino]-3-methylbutyl}-4-ethyl-1,4-dihydrobenzo[1,3]oxazin-2-one

357 mg (1 mmol) of6-benzyloxy-8-(2-ethoxy-2-hydroxyacetyl)-4H-benzo[1,4]oxazin-3-one and530 mg (1 mmol) of1-(3-amino-3-methylbutyl)-4-ethyl-1,4-dihydrobenzo[1,4]oxazine arereacted and worked up analogously to the method described in 5b). Yield:308 mg (46%, trifluoroacetate); mass spectroscopy: [M]⁺=560.

c)4-ethyl-1-{3-[2-hydroxy-2-(6-hydroxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)ethylamino]-3-methylbutyl}-1,4-dihydrobenzo[1,3]oxazin-2-one

308 mg (0.46 mmol) of1-{3-[2-(6-benzyloxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-2-hydroxyethylamino]-3-methylbutyl}-4-ethyl-1,4-dihydrobenzo[1,3]oxazin-2-oneis hydrogenated with palladium on charcoal (10%) as catalyst at ambienttemperature and under 3 bar hydrogen pressure. The catalyst is separatedoff, the filtrate evaporated down and the residue is chromatographed(reverse phase; acetonitrile/water gradient). Yield: 14 mg (5%,trifluoroacetate); mass spectroscopy: [M]⁺=470.

EXAMPLE 78-{2-[1,1-dimethyl-3-(2-oxo-3,4-dihydro-2H-quinolin-1-yl)propylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one

a) 1-(3-amino-3-methylbutyl)-3,4-dihydroquinolin-2-one

Prepared analogously to the method described for Example 6a) from 15.7 g(107 mmol) of 3,4-dihydroquinolin-2-one and 24.9 g (119 mmol) of(3-chloro-1,1-dimethylpropyl)-(1-phenylmethylidene)amine. Unlike in themethod mentioned above, the product is precipitated not as the maleatebut as the hydrochloride. Yield: 6.9 g (24%, hydrochloride); meltingrange: 200° C.-203° C.

b)8-{2-[1,1-dimethyl-3-(2-oxo-3,4-dihydro-2H-quinolin-1-yl)propylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one

Prepared from 357 mg (1 mmol) of6-benzyloxy-8-(2-ethoxy-2-hydroxyacetyl)-4H-benzo[1,4]oxazin-3-one and232 mg (1 mmol) of 1-(3-amino-3-methylbutyl)-3,4-dihydroquinolin-2-oneanalogously to the method described for Example 5c). The finalpurification of the product is carried out by preparative HPLC (reversephase, acetonitrile/water gradient with 0.1% trifluoroacetic acid).Yield: 94 mg (17%, trifluoroacetate); mass spectroscopy: [M]⁺=440.

EXAMPLE 84,4-diethyl-1-{3-[2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]-3-methylbutyl}-1,4-dihydrobenzo[1,3]oxazin-2-one

a)1-{3-[2-(8-benzyloxy-2-oxo-1,2-dihydroquinolin-5-yl)-2-hydroxyethylamino]-3-methylbutyl}-4,4-diethyl-1,4-dihydrobenzo[1,3]oxazin-2-one

400 mg (1.4 mmol) of 8-benzyloxy-5-oxiranylquinolin-2-one and 436 mg(1.5 mmol) of1-(3-amino-3-methylbutyl)-4,4-diethyl-1,4-dihydrobenzo[1,3]oxazin-2-onein 5 mL of n-butanol are stirred for 6 hours at 140° C. The solvent isdistilled off and the residue is purified by chromatography (reversephase; acetonitrile/water gradient). Beige solid. Yield: 160 mg (20%);mass spectroscopy: [M]⁺=584.

b)4,4-diethyl-1-{3-[2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]-3-methylbutyl}-1,4-dihydrobenzo[1,3]oxazin-2-one

160 mg (0.3 mmol) of1-{3-[2-(8-benzyloxy-2-oxo-1,2-dihydroquinolin-5-yl)-2-hydroxyethylamino]-3-methylbutyl}-4,4-diethyl-1,4-dihydrobenzo[1,3]oxazin-2-oneis dissolved in 5 mL of methanol and hydrogenated in the presence ofpalladium on charcoal (10%). Yield: 49 mg (34%); mass spectroscopy:[M]⁺=494.

EXAMPLE 94,4-diethyl-1-{3-[2-hydroxy-2-(6-hydroxy-2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)ethylamino]-3-methylbutyl}-1,4-dihydrobenzo[d][1,3]oxazin-2-one

a) N-(3-acetyl-5-benzyloxy-2-hydroxyphenyl)-2-bromo-2-methylpropionamide

4.64 g (25 mmol) of 2-bromo-2-methylpropionyl chloride are addeddropwise to a solution of 5.15 g (20 mmol) of1-(3-amino-5-benzyloxy-2-hydroxyphenyl)ethanone in 20 mL of pyridine at5° C.-20° C. After the addition has ended, the mixture is stirred for 15minutes, combined with ice water and 100 mL of ethyl acetate andacidified with concentrated hydrochloric acid. The organic phase isseparated off, washed with water, and dried with sodium sulfate. Afterthe solvent has been distilled off, the residue is crystallized from adiethyl ether/petroleum ether mixture. Yield: 6.8 g (84%); meltingrange: 88° C.-90° C.

b) 8-acetyl-6-benzyloxy-2,2-dimethyl-4H-benzo[1,4]oxazin-3-one

6.60 g (16.2 mmol) ofN-(3-acetyl-5-benzyloxy-2-hydroxyphenyl)-2-bromo-2-methylpropionamideand 2.76 g (20 mmol) of potassium carbonate are stirred for 1 hour in 70mL acetonitrile at reflux temperature. The solid is suction filtered,the filtrate is evaporated down, and the residue is combined with 30 mLof ethyl acetate. After fresh filtration and distilling off the solvent,the crude product is crystallized from a little methanol. Yield: 1.00 g(19%); mass spectroscopy [M+H]⁺=326; melting range=148° C.-150° C.

c)6-benzyloxy-8-(2-ethoxy-2-hydroxyacetyl)-2,2-dimethylbenzo[1,4]oxazin-3-one

50.12 g (154 mmol) is8-acetyl-6-benzyloxy-2,2-dimethylbenzo[1,4]oxazin-3-one is reacted withselenium dioxide as oxidizing agent and activated charcoal in refluxingdioxane and some water. After cooling, the solid is filtered off andwashed with dioxane. The filtrate is evaporated down and the residue isdissolved in 550 mL of ethanol and refluxed for 30 minutes. It isfiltered and the mother liquor is cooled to −18° C., during which time asolid is precipitated which is suction filtered. After recrystallizationfrom ethanol, the product is obtained in the form of a beige solid.Yield: 8.95 g (15%).

d)1-{3-[2-(6-benzyloxy-2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-2-hydroxyethylamino]-3-methylbutyl}-4,4-diethyl-1,4-dihydrobenzo[d][1,3]oxazin-2-one

Prepared from 406 mg (1 mmol) of6-benzyloxy-8-(2-ethoxy-2-hydroxyacetyl)-2,2-dimethylbenzo[1,4]oxazin-3-oneand 290 mg (1 mmol) of1-(3-amino-3-methylbutyl)-4,4-diethyl-1,4-dihydrobenzo[1,3]oxazin-2-oneanalogously to the method described for Example 5b). The target compoundis purified by chromatography with silica gel on a short column(dichloromethane/methanol gradient). White solid. Yield: 145 mg (24%);mass spectroscopy [M+H]⁺=616.

e)4,4-diethyl-1-{3-[2-hydroxy-2-(6-hydroxy-2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)ethylamino]-3-methylbutyl}-1,4-dihydrobenzo[d][1,3]oxazin-2-one

130 mg (0.21 mmol)1-{3-[2-(6-benzyloxy-2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-2-hydroxyethylamino]-3-methylbutyl}-4,4-diethyl-1,4-dihydrobenzo[d][1,3]oxazin-2-oneare dissolved in 5 mL methanol and hydrogenated in the presence ofpalladium on charcoal (10%) at ambient temperature. The catalyst issuction filtered, the filtrate is evaporated down and the residue ispurified by chromatography (Reverse phase; acetonitrile/water gradient).White solid. Yield: 41 mg (37%); mass spectroscopy [M+H]⁺=526.

EXAMPLE 104,4-diethyl-1-{3-[2-hydroxy-2-(5-hydroxy-2-oxo-2,3-dihydrobenzooxazol-7-yl)ethylamino]-3-methylbutyl}-1,4-dihydrobenzo[d][1,3]oxazin-2-one

a) 7-acetyl-5-benzyloxy-3H-benzooxazol-2-one

51.1 mL (97.04 mmol) of a phosgene solution (20% by weight in toluene)are added at 0° C. to a solution of 22.7 g (88.22 mmol) of1-(3-amino-5-benzyloxy-2-hydroxyphenyl)ethanone in toluene (200 mL).Then 30.7 mL (220.6 mmol) of triethylamine is added dropwise such thatthe temperature does not exceed 5° C. After 1 hour stirring at ambienttemperature, a further 4.6 mL of phosgene solution and 12 mL oftriethylamine are added at 0° C. The mixture is stirred for 1 hour atambient temperature, diluted with dichloromethane and combined withsaturated aqueous ammonium chloride solution (500 mL) and 2 N aqueoushydrochloric acid (10 mL). After the aqueous phase has been separatedoff it is exhaustively extracted with dichloromethane. The combinedorganic phases are washed with water and saturated aqueous sodiumchloride solution, dried with sodium sulfate and evaporated down invacuo, during which time a beige solid is precipitated. The precipitateis filtered off, washed with a little toluene, and dried at 50° C. invacuo. Yield: 18.5 g (74%); R_(f)=0.19 (silica gel, toluene/acetone95:10); ESI-MS: [M+H]⁺=284.

b) 5-benzyloxy-7-(2-ethoxy-2-hydroxyacetyl)-3H-benzooxazol-2-one

14.4 mL (127.1 mmol) of HBr (48% in water) are added to a solution of12.0 g (42.4 mmol) of 7-acetyl-5-benzyloxy-3H-benzooxazol-2-one in DMSO(60 mL). The mixture is stirred for 6 hours at 60° C. under a gentlenitrogen current, poured onto 600 mL of ice water and stirred for 20minutes. The precipitate formed is filtered off and washed with icewater and cold water/ethyl acetate solution (1:1). The precipitate isdissolved in 300 mL of ethanol and 100 mL of ethyl acetate andevaporated down in vacuo. The process is repeated with 500 mL of tolueneand then with 500 mL of ethanol. The residue is then dissolved in 250 mLof ethanol and refluxed for 1 hour. After 30 mL of ethanol has beendistilled off, the mixture is cooled to ambient temperature and then to0° C. The precipitate formed is filtered off, washed with 80 mL ofice-cold ethanol and 200 mL of ether, and dried at 50° C. in vacuo.Yield: 6.5 g (45%); R_(f)=0.23 (silica gel, dichloromethane/MeOH 25:2);ESI-MS: [M+H—CO₂Et]⁺=270.

c)1-{3-[2-(5-benzyloxy-2-oxo-2,3-dihydrobenzooxazol-7-yl)-2-hydroxyethylamino]-3-methylbutyl}-4,4-diethyl-1,4-dihydrobenzo[d][1,3]oxazin-2-one

Obtained from 343 mg (1 mmol) of5-benzyloxy-7-(2-ethoxy-2-hydroxyacetyl)-3H-benzooxazol-2-one and 290 mg(1 mmol) of1-(3-amino-3-methylbutyl)-4,4-diethyl-1,4-dihydrobenzo[1,3]oxazin-2-oneaccording to the method described for Example 5b). White solid. Yield:160 mg (28%); mass spectroscopy [M−H]⁺=572.

d)4,4-diethyl-1-{3-[2-hydroxy-2-(5-hydroxy-2-oxo-2,3-dihydrobenzooxazol-7-yl)ethylamino]-3-methylbutyl}-1,4-dihydrobenzo[d][1,3]oxazin-2-one

150 mg (0.26 mmol) of1-{3-[2-(5-benzyloxy-2-oxo-2,3-dihydrobenzooxazol-7-yl)-2-hydroxyethylamino]-3-methylbutyl}-4,4-diethyl-1,4-dihydrobenzo[d][1,3]oxazin-2-oneis dissolved in 5 mL of methanol and hydrogenated with palladium oncharcoal as catalyst for 3 hours at ambient temperature. The catalyst isseparated off and the filtrate is evaporated down. Beige solid. Yield:116 mg (92%); mass spectroscopy [M−H]⁺=484.

HPLC method (method A): Symmetry C18 (Waters); 3.5 μm; 4.6×150 mm;Column temperature: 20° C.; gradient acetonitrile/phosphate buffer (pH7) 20:80→80:20 in 30 min., flow: 1.0 mL/min; detection at 220 and 254nm.

EXAMPLE 114,4-diethyl-1-{3-[2-hydroxy-2-(7-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]-3-methylbutyl}-1,4-dihydrobenzo[d][1,3]oxazin-2-one

a) 2-acetyl-4-benzyloxy-6-nitrophenyl trifluoromethanesulfonate

Triethylamine (92.7 mL, 0.660 mol) is added to a solution of1-(5-benzyloxy-2-hydroxy-3-nitrophenyl)ethanone (90.0 g, 0.313 mol) inabsolute dichloromethane (940 mL) at −10° C. within 10 minutes. Asolution of trifluoromethanesulfonic anhydride (65 mL, 0.394 mol) inabsolute dichloromethane (40 mL) is added to this red solution within 15minutes and the resulting mixture is stirred for a further 5 minutes at−5° C. The brown solution is washed with saturated aqueous ammoniumchloride (400 mL) and saturated aqueous NaCl (400 mL) and the phases areseparated. Drying with sodium sulfate and evaporation in vacuo yieldsthe crude product as an oil which becomes solid when left to stand. Thecrude product is dissolved in ether (150 mL), the solution is combinedwith hexane (800 mL), and the precipitate formed is filtered off. Thesolid is stirred with ether/hexane (80/20, 100 mL), filtered off anddried in the oven at 40° C. Yield: 118 g (90%); ESI-MS: [M+H]⁺=420.

b) methyl 3-(2-acetyl-4-benzyloxy-6-nitrophenyl)acrylate

100 g of molecular sieve (4 Å), tris(dibenzylideneacetone)dipalladium(5.88 g, 6.42 mmol), tri-tert-butylphosphonium-tetrafluoroborate (3.50g, 12.06 mmol), dicyclohexylmethylamine (81.2 mL, 0.371 mol), driedtetrabutylammonium iodide (105.8 g, 0.286 mol), and methyl acrylate(32.6 mL, 0.362 mol) are added to a solution of2-acetyl-4-benzyloxy-6-nitrophenyl trifluoromethanesulfonate (100.0 g,0.238 mol) in dioxane (360 mL) under a nitrogen atmosphere. The reactionmixture is stirred for 2 hours at 80° C., diluted with ether (2 L) andcombined with 500 g silica gel. The suspension is stirred for 10minutes, filtered, and the silica gel is washed several times with ether(4×600 mL). The combined organic phases are washed with 1 M aqueoushydrochloric acid (300 mL), sodium bicarbonate solution, and sodiumchloride solution, dried with sodium sulfate, and evaporated down. Theoily crude product is recrystallized from hot ethanol (0.75 L). Theprecipitate is filtered off, washed with ethanol (2×50 mL) and dried at40° C. Yield: 32.2 g (38%); mass spectroscopy: [M+H]⁺=356.

c) 5-acetyl-7-benzyloxy-3,4-dihydro-1H-quinolin-2-one

A suspension of methyl 3-(2-acetyl-4-benzyloxy-6-nitrophenyl)acrylate(5.0 g, 14.07 mmol) in ethanol (100 mL) is hydrogenated with Raneynickel (3 g) at ambient temperature and 4 bar hydrogen pressure. After 6hours, more Raney nickel (2 g) is added and the mixture is hydrogenatedfor a further 2 hours. The catalyst is separated off and the filtrate iscombined with 2 M aqueous hydrochloric acid (15 mL). The product thatcrystallizes out is filtered off and dried. Yield: 1.0 g (24%); massspectroscopy: [M+H]⁺=296.

d) 5-acetyl-7-benzyloxy-1H-quinolin-2-one

DDQ (15.0 g, 66.08 mmol) is added to a suspension of5-acetyl-7-benzyloxy-3,4-dihydro-1H-quinolin-2-one (13.0 g, 44.02 mmol)in dioxane (130 mL) and the mixture is refluxed for 30 minutes. Thereaction mixture is cooled to ambient temperature and stirred for afurther 2 hours. The precipitate formed is filtered off, washed withdioxane (2×20 mL) and dissolved in dichloromethane/methanol (9:1, 600mL). The organic phase is washed with sodium bicarbonate solution (2×100mL), dried with sodium sulfate, and evaporated down. The residue isstirred with methanol, the precipitate formed is filtered off and dried.Yield: 8.3 g (64%); mass spectroscopy: [M+H]⁺=294.

e) 7-benzyloxy-5-(2-chloroacetyl)-1H-quinolin-2-one

5-acetyl-7-benzyloxy-1H-quinolin-2-one (7.0 g, 23.86 mmol) is dissolvedin a mixture of 1,2-dichloroethane (147 mL), glacial acetic acid (43mL), and water (7 mL) and combined withN-benzyltrimethylammonium-dichloriodate (19.0 g, 54.58 mmol). Themixture is stirred for 4.5 hours at 65° C., then diluted with sodiumbicarbonate solution and 5% sodium bisulfite solution and stirred for 5minutes. The precipitate formed is filtered off, washed with water (2×20mL) and dried in the oven. Yield: 6.0 g (77%); mass spectroscopy:

[M+H]⁺=328.

f) 7-benzyloxy-5-oxiranyl-1H-quinolin-2-one

Lithium borohydride (434 mg, 19.93 mmol) is added to a suspension of7-benzyloxy-5-(2-chloroacetyl)-1H-quinolin-2-one (6 g, 18.31 mmol) inTHF (150 mL) at 0° C.-5° C. and the mixture is stirred for 30 minutes.2.5 N sodium hydroxide solution (43 mL, 107.50 mmol) is added and themixture is stirred for 2 hours at 5° C.-10° C. and for 2.5 hours atambient temperature. Then the reaction mixture is slowly combined withglacial acetic acid (6.5 mL) followed by semisaturated sodium chloridesolution (100 mL) and stirred for a further 5 minutes. The precipitateformed is filtered off and the aqueous phase is extracted with ethylacetate/THF (1/1.5×100 mL). The solid filtered off and the organicphases are combined, dried with sodium sulfate, and evaporated down. Thecrude product is stirred with methanol (30 mL) and the precipitate isfiltered off and dried at ambient temperature. Yield: 4.8 g (89%); massspectroscopy: [M+H]⁺=294.

g)1-{3-[2-(7-benzyloxy-2-oxo-1,2-dihydroquinolin-5-yl)-2-hydroxyethylamino]-3-methylbutyl}-4,4-diethyl-1,4-dihydrobenzo[d][1,3]oxazin-2-one

A suspension of 7-benzyloxy-5-oxiranyl-1H-quinolin-2-one (112 mg, 0.382mmol) and1-(3-amino-3-methylbutyl)-4,4-diethyl-1,4-dihydrobenzo[d][1,3]oxazin-2-one(220 mg, 0.758 mmol) in isopropanol (1.0 mL) is heated in the microwavefor 1 hour to 135° C. The mixture is diluted with EtOAc (10 mL) andwashed with 0.5 M aqueous tartaric acid solution, whereupon half theproduct is precipitated. The phases are separated and the aqueoussuspension is combined with MeOH until a clear solution is obtainedagain. The aqueous phase is extracted with dichloromethane and thecombined organic phases are dried with sodium sulfate and evaporateddown in vacuo. The residue is stirred with EtOAc and the precipitate isfiltered off and dried in vacuo. Yield: 152 mg (68%); HPLC-MS:R_(t)=14.8 min. (method A).

h)4,4-diethyl-1-{3-[2-hydroxy-2-(7-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]-3-methylbutyl}-1,4-dihydrobenzo[d][1,3]oxazin-2-one

A suspension of1-{3-[2-(7-benzyloxy-2-oxo-1,2-dihydroquinolin-5-yl)-2-hydroxyethylamino]-3-methylbutyl}-4,4-diethyl-1,4-dihydrobenzo[d][1,3]oxazin-2-one(152 mg, 0.338 mmol) and Pd/C (10%) (40 mg) in MeOH (12 mL) ishydrogenated at room temperature (RT) and 1 bar hydrogen pressure for 4hours. The catalyst is filtered off through CELITE® filter aid andwashed with MeOH (5 mL). The organic phase is evaporated down, theresidue is triturated with EtOAc and the precipitate formed is filteredoff and dried in vacuo. Yield: 76 mg (46%); R_(f)=0.3 (silica gel,dichloromethane/MeOH/saturated aqueous ammonia 90:10:0.5); ESI-MS:[M+H]⁺=494.

Specific starting compounds are needed for the examples of synthesisthat follow. Their preparation is described hereinafter.

Intermediate Product 1:1-(3-amino-3-methylbutyl)-4,4-dipropyl-1,4-dihydrobenzo[d][1,3]oxazin-2-onehydrochloride

a) 4-(2-aminophenyl)heptan-4-ol

90.0 mL (180.00 mmol) of propylmagnesium chloride (2 M in ether) isadded dropwise within 30 minutes to a solution of 7.00 mL (54.04 mmol)methyl anthranilate in absolute THF (70 mL) at 0° C. The mixture isstirred for 1 hour at RT and then combined with 100 mL of 3 M aqueousammonium chloride solution and EtOAc. The phases are separated and theaqueous phase is exhaustively extracted with EtOAc. The combined organicphases are washed with aqueous KHCO₃ and saturated aqueous NaCl anddried with sodium sulfate. The crude product is used in the nextreaction step without any further purification. Yield: 6.70 g (60%).

b) tert-butyl{3-[2-(1-hydroxy-1-propylbutyl)phenylamino]-1,1-dimethylpropyl}carbamate

1.40 g (22.27 mmol) of sodium cyanoborohydride is added to a solution of3.10 g (14.05 mmol) of 4-(2-aminophenyl)heptan-4-ol and 3.60 g (17.88mmol) of tert-butyl (1,1-dimethyl-3-oxopropyl)carbamate in MeOH (40 mL)and AcOH (6 mL). The mixture is stirred for 16 hours at RT, diluted withEtOAc, and washed with 0.5 M aqueous KHSO₄ and saturated aqueous NaCl,dried with sodium sulfate, and evaporated down in vacuo. The crudeproduct is used in the next reaction step without any furtherpurification. Yield: 6.00 g (quantitative yield).

c)tert-butyl[1,1-dimethyl-3-(2-oxo-4,4-dipropyl-4H-benzo[d][1,3]oxazin-1-yl)propyl]carbamate

8.85 mL (16.81 mmol) of phosgene solution (20 wt. % in toluene) isslowly added dropwise at 0° C. to a solution of 6.00 g (15.28 mmol) oftert-butyl{3-[2-(1-hydroxy-1-propylbutyl)phenylamino]-1,1-dimethylpropyl}carbamateand 5.32 mL (38.21 mmol) of triethylamine in absolute THF (80 mL). Themixture is stirred for 2 hours at RT, diluted with EtOAc, combined withice, and made basic with saturated aqueous ammonia solution. The aqueousphase is exhaustively extracted with EtOAc and the combined organicphases are washed with saturated aqueous NaCl, dried with sodiumsulfate, and evaporated down in vacuo. After column chromatography(silica gel, cyclohexane/EtOAc 6:1) the product is obtained as a yellowoil. Yield: 4.57 g (71%).

d)1-(3-amino-3-methylbutyl)-4,4-dipropyl-1,4-dihydrobenzo[d][1,3]oxazin-2-onehydrochloride

A solution of 4.20 g (10.03 mmol) oftert-butyl[1,1-dimethyl-3-(2-oxo-4,4-dipropyl-4H-benzo[d][1,3]oxazin-1-yl)propyl]carbamatein 35 mL of formic acid is stirred for 24 hours at RT and then pouredonto ice. The aqueous phase is made basic with saturated aqueous ammoniasolution and exhaustively extracted with EtOAc. The combined organicextracts are washed with saturated aqueous NaCl, dried with sodiumsulfate, and evaporated down in vacuo. The residue is taken up in EtOAc(50 mL) and combined with 4 mL HCl solution (saturated in EtOAc). Thesolution is concentrated by evaporation and twice combined with a littleEtOH and evaporated down in vacuo. Trituration of the residue withdiisopropylether yields the product as a hygroscopic hydrochloride salt.Yield: 2.60 g (73%).

Intermediate product 2:1-(3-amino-3-methylbutyl)-4,4-diethyl-7-fluoro-1,4-dihydrobenzo[d][1,3]oxazin-2-one

a) 3-(2-amino-4-fluorophenyl)pentan-3-ol

The product is obtained analogously to intermediate product 1a byreacting methyl 2-amino-4-fluorobenzoate and ethylmagnesium bromide indichloromethane at −78° C.→RT. Yield: 4.1 g (99%).

b) tert-butyl{3-[2-(1-ethyl-1-hydroxypropyl)-5-fluorophenylamino]-1,1-dimethylpropyl}carbamate

The product is obtained analogously to intermediate product 1b startingfrom 3-(2-amino-4-fluorophenyl)pentan-3-ol and tert-butyl(1,1-dimethyl-3-oxopropyl)carbamate. The crude product is purified bycolumn chromatography (silica gel, dichloromethane/MeOH 100:0→98:2).Yield: 7.70 g (99%).

c)tert-butyl[3-(4,4-diethyl-7-fluoro-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-1,1-dimethylpropyl]carbamate

The product is obtained analogously to intermediate product 1c startingfrom tert-butyl{3-[2-(1-ethyl-1-hydroxypropyl)-5-fluorophenylamino]-1,1-dimethylpropyl}carbamate.Yield: 4.20 g (51%).

d)1-(3-amino-3-methylbutyl)-4,4-diethyl-7-fluoro-1,4-dihydrobenzo[d][1,3]oxazin-2-one

The product is obtained analogously to intermediate product 1d startingfromtert-butyl[3-(4,4-diethyl-7-fluoro-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-1,1-dimethylpropyl]carbamateas the free base. Yield: 2.90 g (96%); ESI-MS: [M+H]⁺=309.

Intermediate Product 3:1-(3-amino-3-methylbutyl)-4,4-diethyl-8-methoxy-1,4-dihydrobenzo[d][1,3]oxazin-2-one

a) 3-(2-amino-3-methoxyphenyl)pentan-3-ol

The product is obtained analogously to intermediate product 1a byreacting methyl 2-amino-3-methoxybenzoate and ethylmagnesium bromide indichloromethane at −78° C.→RT. Yield: 5.20 g (92%); HPLC-MS: R_(t)=12.85min. (method A); ESI-MS: [M+H]⁺=210.

b) tert-butyl{3-[2-(1-ethyl-1-hydroxypropyl)-6-methoxyphenylamino]-1,1-dimethylpropyl}carbamate

The product is obtained analogously to intermediate product 1b startingfrom 3-(2-amino-3-methoxyphenyl)pentan-3-ol and tert-butyl(1,1-dimethyl-3-oxopropyl)carbamate. The crude product is purified bycolumn chromatography (silica gel, cyclohexane/EtOAc, 4:1). Yield: 4.60g (47%).

c)tert-butyl[3-(4,4-diethyl-8-methoxy-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-1,1-dimethylpropyl]carbamate

The product is obtained analogously to intermediate product 1c startingfrom tert-butyl{3-[2-(1-ethyl-1-hydroxypropyl)-6-methoxyphenylamino]-1,1-dimethylpropyl}carbamate.Yield: 4.60 g (94%).

d)1-(3-amino-3-methylbutyl)-4,4-diethyl-8-methoxy-1,4-dihydrobenzo[d][1,3]oxazin-2-one

The product is prepared as the free base analogously to intermediateproduct 1d starting fromtert-butyl[3-(4,4-diethyl-8-methoxy-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-1,1-dimethylpropyl]carbamate.Yield: 3.00 g (93%); ESI-MS: [M+H]⁺=321.

Intermediate Product 4:1-(3-amino-3-methylbutyl)spiro(cyclohexane-1,4′-2H-3′,1′-benzoxazin)-2′-one

a) 1-(2-nitrophenyl)cyclohexanol

40.16 mL (80.32 mmol) of phenylmagnesium chloride (2 M in THF) is addeddropwise at −50° C. to a solution of 20.0 g (80.32 mmol) of2-nitroiodobenzene in absolute THF (150 mL) under a nitrogen atmosphere.After stirring for 15 minutes, 9.98 mL (96.30 mmol) of cyclohexanone isadded quickly. The mixture is heated to RT and stirred for a further 2hours. Saturated aqueous ammonium chloride solution is added and theaqueous phase is exhaustively extracted with EtOAc. The combined organicextracts are washed with saturated aqueous NaCl solution, dried withsodium sulfate, and evaporated down in vacuo. After columnchromatography (silica gel, hexane/EtOAc 20:1), the product is obtainedas a brownish oil. Yield: 5.20 g (29%); R_(f)=0.26 (silica gel,hexane/EtOAc 10:1); ESI-MS: [M+H—H₂O]⁺=204.

b) 1-(2-aminophenyl)cyclohexanol

A suspension of 5.20 g (16.45 mmol) of 1-(2-nitrophenyl)cyclohexanol and500 mg of Raney nickel in EtOH (70 mL) is hydrogenated at RT and under 3bar hydrogen pressure for 4 hours. The catalyst is filtered off throughCELITE® filter aid and the filtrate is evaporated down in vacuo. Theresidue is recrystallized from hexane. Yield: 1.53 g (49%); R_(f)=0.38(silica gel, hexane/EtOAc 4:1); ESI-MS: [M+H—H₂O]⁺=174.

c) tert-butyl{3-[2-(1-hydroxycyclohexyl)phenylamino]-1,1-dimethylpropyl}carbamate

The product is prepared analogously to intermediate product 1b startingfrom 1-(2-aminophenyl)cyclohexanol and tert-butyl(1,1-dimethyl-3-oxopropyl)carbamate. After column chromatography (silicagel, hexane/EtOAc 7:1) the product is obtained as a colorless oil.Yield: 2.65 g (66%); R_(f)=0.50 (silica gel, hexane/EtOAc 4:1).

d)tert-butyl[3-(spiro(cyclohexane-1,4′-2H-3′,1′-benzoxazin)-2′-oxo-1-yl)-1,1-dimethylpropyl]carbamate

The product is prepared analogously to intermediate product 1c startingfrom tert-butyl{3-[2-(1-hydroxycyclohexyl)phenylamino]-1,1-dimethylpropyl}carbamate.Yield: 2.60 g (92%); R_(f)=0.38 (silica gel, hexane/EtOAc 4:1).

e)1-(3-amino-3-methylbutylspiro(cyclohexane-1,4′-2H-3′,1′-benzoxazin)-2′-one

The product is prepared analogously to intermediate product 1d startingfromtert-butyl[3-(spiro(cyclohexane-1,4′-2H-3′,1′-benzoxazin)-2′-oxo-1-yl)-1,1-dimethylpropyl]carbamate.Yield: 1.80 g (92%); R_(f)=0.10 (silica gel,dichloromethane/MeOH/saturated aqueous ammonia 95:5:0.5); ESI-MS:[M+H]⁺=303.

EXAMPLE 121-{3-[2-hydroxy-2-(6-hydroxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)ethylamino]-3-methylbutyl}-4,4-dipropyl-1,4-dihydrobenzo[d][1,3]oxazin-2-one

a)1-{3-[2-(6-benzyloxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-2-hydroxyethylamino]-3-methylbutyl}-4,4-dipropyl-1,4-dihydrobenzo[d][1,3]oxazin-2-one

86 μL (0.619 mmol) of triethylamine is added to a solution of 200 mg(0.564 mmol) of1-(3-amino-3-methylbutyl)-4,4-dipropyl-1,4-dihydrobenzo[d][1,3]oxazin-2-onehydrochloride in absolute THF (5 mL) at RT under a nitrogen atmosphereand the mixture is stirred for 30 minutes, 200 mg (0.560 mmol) of6-benzyloxy-8-(2-ethoxy-2-hydroxyacetyl)-4H-benzo[1,4]oxazin-3-one isadded and the mixture is stirred for another 2 h at RT. The mixture iscooled to 10° C., combined with 51 mg (2.34 mmol) of lithiumborohydride, heated to RT, and stirred for 1 hour at RT. It is againcooled to 10° C. and slowly combined with 15 mL water and 20 mLdichloromethane. The phases are separated and the aqueous phase isextracted with dichloromethane. The combined organic phases are driedwith sodium sulfate and evaporated down in vacuo. The residue isdissolved in EtOAc (8 mL) and acidified to pH 2 by the addition of HClsolution (saturated in EtOAc). The precipitate formed is filtered off,washed with EtOAc and dried in vacuo. Yield: 270 mg (74%;hydrochloride), HPLC-MS: R_(t)=18.7 min. (method A).

b)1-{3-[2-hydroxy-2-(6-hydroxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)ethylamino]-3-methylbutyl}-4,4-dipropyl-1,4-dihydrobenzo[d][1,3]oxazin-2-one

A suspension of 270 mg (0.438 mmol)1-{3-[2-(6-benzyloxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-2-hydroxyethylamino]-3-methylbutyl}-4,4-dipropyl-1,4-dihydrobenzo[d][1,3]oxazin-2-oneand 27 mg Pd/C (10%) in MeOH (8 mL) is hydrogenated at RT and 1 barhydrogen pressure for 3 hours. The catalyst is filtered off throughCELITE® filter aid and washed with MeOH (5 mL) and the filtrate isconcentrated by evaporation in vacuo. The residue is dissolved inEtOAc/dichloromethane (1:1, 10 mL), acidified to pH 2 by the addition ofHCl solution (saturated in EtOAc) and concentrated by evaporation invacuo. The residue is triturated with ether, filtered and dried invacuo. Yield: 80 mg (33%; hydrochloride), HPLC-MS: R_(t)=12.8 min.(method A), ESI-MS: [M+H]⁺=526.

EXAMPLE 131-{3-[2-hydroxy-2-(5-hydroxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)ethylamino]-3-methylbutyl}-4,4-dipropyl-1,4-dihydrobenzo[d][1,3]oxazin-2-one

a)1-{3-[2-(5-benzyloxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-2-hydroxyethylamino]-3-methylbutyl}-4,4-dipropyl-1,4-dihydrobenzo[d][1,3]oxazin-2-one

The product is prepared analogously to Example 12a starting from5-benzyloxy-8-(2,2-dihydroxyacetyl)-4H-benzo[1,4]oxazin-3-one and1-(3-amino-3-methylbutyl)-4,4-dipropyl-1,4-dihydrobenzo[d][1,3]oxazin-2-onehydrochloride. The crude product is dissolved in EtOAc, washed with 5%aqueous NaOH solution, and purified by column chromatography (silicagel, dichloromethane/MeOH 98:2→90:10). Yield: 170 mg (49%); HPLC-MS:R_(t)=18.9 min. (method A).

b)1-{3-[2-hydroxy-2-(5-hydroxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)ethylamino]-3-methylbutyl}-4,4-dipropyl-1,4-dihydrobenzo[d][1,3]oxazin-2-one

The product is prepared analogously to Example 12b starting from1-{3-[2-(5-benzyloxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-2-hydroxyethylamino]-3-methylbutyl}-4,4-dipropyl-1,4-dihydrobenzo[d][1,3]oxazin-2-one.Yield: 30 mg (19%, hydrochloride); HPLC-MS: R_(t)=13.0 min. (method A);ESI-MS: [M+H]⁺=526.

EXAMPLE 144,4-diethyl-7-fluoro-1-{3-[2-hydroxy-2-(6-hydroxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)ethylamino]-3-methylbutyl}-1,4-dihydrobenzo[d][1,3]oxazin-2-one

a)1-{3-[2-(6-benzyloxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-2-hydroxyethylamino]-3-methylbutyl}-4,4-diethyl-7-fluoro-1,4-dihydrobenzo[d][1,3]oxazin-2-one

A solution of 232 mg (0.649 mmol) of6-benzyloxy-8-(2-ethoxy-2-hydroxyacetyl)-4H-benzo[1,4]oxazin-3-one and200 mg (0.649 mmol) of1-(3-amino-3-methylbutyl)-4,4-diethyl-7-fluoro-1,4-dihydrobenzo[d][1,3]oxazin-2-onein absolute THF (5 mL) is stirred for 2.5 hours at RT. The mixture iscooled to 5° C., combined with 60 mg (2.755 mmol) lithium borohydride,heated to RT, and stirred for 1 hour. The mixture is again cooled to 5°C. and slowly diluted with 15 mL of water and 20 mL of dichloromethane.The phases are separated and the aqueous phase is extracted withdichloromethane. The combined organic phases are dried with sodiumsulfate and concentrated by evaporation in vacuo. The residue ispurified by column chromatography (silica gel, dichloromethane/MeOH95:5). Yield: 257 mg (65%); HPLC-MS: R_(t)=16.5 min. (method A).

b)4,4-diethyl-7-fluoro-1-{3-[2-hydroxy-2-(6-hydroxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)ethylamino]-3-methylbutyl}-1,4-dihydrobenzo[d][1,3]oxazin-2-one

The product is prepared analogously to Example 12b starting from1-{3-[2-(6-benzyloxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-2-hydroxyethylamino]-3-methylbutyl}-4,4-diethyl-7-fluoro-1,4-dihydrobenzo[d][1,3]oxazin-2-one.Yield: 170 mg (78%; hydrochloride); HPLC-MS: R_(t)=10.6 min. (method A);ESI-MS: [M+H]⁺=516.

EXAMPLE 154,4-diethyl-1-{3-[2-hydroxy-2-(5-hydroxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)ethylamino]-3-methylbutyl}-8-methoxy-1,4-dihydrobenzo[d][1,3]oxazin-2-one

a)1-{3-[2-(5-benzyloxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-2-hydroxyethylamino]-3-methylbutyl}-4,4-diethyl-8-methoxy-1,4-dihydrobenzo[d][1,3]oxazin-2-one

The product is prepared analogously to Example 14a starting from5-benzyloxy-8-(2,2-dihydroxyacetyl)-4H-benzo[1,4]oxazin-3-one and1-(3-amino-3-methylbutyl)-4,4-diethyl-8-methoxy-1,4-dihydrobenzo[d][1,3]oxazin-2-one.The crude product is purified by column chromatography (silica gel,dichloromethane/MeOH 95:5). Yield: 70 mg (18%); HPLC-MS: R_(t)=16.5 min.(method A).

b)4,4-diethyl-1-{3-[2-hydroxy-2-(5-hydroxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)ethylamino]-3-methylbutyl}-8-methoxy-1,4-dihydrobenzo[d][1,3]oxazin-2-one

The product is obtained analogously to Example 12b starting from1-{3-[2-(5-benzyloxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-2-hydroxyethylamino]-3-methylbutyl}-4,4-diethyl-8-methoxy-1,4-dihydrobenzo[d][1,3]oxazin-2-one.Yield: 40 mg (62%); HPLC-MS: R_(t)=13.3 min. (method A); ESI-MS:[M+H]⁺=528.

EXAMPLE 161-(2-{1-[2-hydroxy-2-(5-hydroxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)ethylamino]cyclopropyl}ethyl)-4,4-dimethyl-1,4-dihydrobenzo[d][1,3]oxazin-2-one

a) 3-(4,4-dimethyl-2-oxo-4H-benzo[d][1,3]oxazin-1-yl]propionitrile

10.2 mL (123 mmol) of bromopropionitrile is added dropwise to a solutionof 20.0 g (112 mmol) of4,4-dimethyl-1,4-dihydrobenzo[d][1,3]oxazin-2-one and 17.4 g (126 mmol)of potassium carbonate in 250 mL of acetonitrile and the mixture isrefluxed overnight. Another 4 mL (48 mmol) of bromopropionitrile isadded and the mixture is refluxed for another 2 hours. The solid issuction filtered, the filtrate is evaporated down, and the residue isrecrystallized from diisopropylether. White solid. Yield: 22.8 g (88%);mass spectroscopy: [M+H]⁺=231.

b)1-[2-(1-aminocyclopropyl)ethyl]-4,4-dimethyl-1,4-dihydrobenzo[d][1,3]oxazin-2-one

A suspension of 6.0 g (26 mmol) of3-(4,4-dimethyl-2-oxo-4H-benzo[d][1,3]oxazin-1-yl]propionitrile in 120mL of diethyl ether is combined with 16.5 mL (56 mmol) of titaniumtetraisopropoxide while being cooled with an ice bath. Then 18.5 mL of a3 molar solution of ethylmagnesium bromide in diethyl ether is addeddropwise such that the temperature does not climb past 20° C. Themixture is stirred for 30 minutes at ambient temperature and 7.0 mL (55mmol) boron trifluoride-diethyl ether is added batchwise while coolingwith an ice bath. The mixture is stirred for one hour at ambienttemperature and 150 mL of a 1 molar sodium hydroxide solution is addeddropwise while cooling. The reaction mixture is diluted with diethylether and the phases are separated. The aqueous phase is extracted withdiethyl ether and the combined organic phases are extracted with sodiumsulfite solution and repeatedly extracted with 1 molar hydrochloricacid. The hydrochloric acid phases are combined, extracted with diethylether, made alkaline with sodium hydroxide solution, and exhaustivelyextracted with dichloromethane. The dichloromethane phases are driedwith sodium sulfate and evaporated down. Light yellow oil. Yield: 1.5 g(22%); mass spectroscopy: [M+H]⁺=261.

c)1-(2-{1-[2-(5-benzyloxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-2-hydroxyethylamino]cyclopropyl}ethyl)-4,4-dimethyl-1,4-dihydrobenzo[d][1,3]oxazin-2-one

900 mg (2.5 mmol) of5-benzyloxy-8-(2-ethoxy-2-hydroxyacetyl)-4H-benzo[1,4]oxazin-3-one and700 mg (2.7 mmol) of1-[2-(1-aminocyclopropyl)ethyl]-4,4-dimethyl-1,4-dihydrobenzo[d][1,3]oxazin-2-oneis dissolved in 20 mL of ethanol and stirred in each case for 30 minutesat 80° C. and 50° C. The reaction mixture is cooled, combined with 200mg (5.3 mmol) sodium borohydride, and stirred for 2 hours at ambienttemperature. Glacial acetic acid is added, the mixture is stirred for 10minutes, and evaporated down. The residue is taken up in dichloromethaneand washed successively with potassium hydrogen sulfate solution, 15%potassium carbonate solution, and sodium hydrogen carbonate solution.Then the organic phase is dried with sodium sulfate and freed fromsolvent. The residue is purified by column chromatography (silica gel;ethyl acetate/methanol/ammonia gradient). Recrystallization fromdiisopropylether. White solid. Yield: 690 mg (49%); mass spectroscopy:[M+H]⁺=558.

d)1-(2-{1-[2-hydroxy-2-(5-hydroxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)ethylamino]cyclopropyl}ethyl)-4,4-dimethyl-1,4-dihydrobenzo[d][1,3]oxazin-2-one

650 mg (1.17 mmol) of1-(2-{1-[2-(5-benzyloxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-2-hydroxyethylamino]cyclopropyl}ethyl)-4,4-dimethyl-1,4-dihydrobenzo[d][1,3]oxazin-2-oneis dissolved in 30 mL of methanol, combined with palladium on charcoal(10%), and hydrogenated at ambient temperature and 3 bar hydrogenpressure. Yield: 240 mg (44%); mass spectroscopy: [M+H]⁺=468.

EXAMPLE 171-(2-{1-[2-hydroxy-2-(6-hydroxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)ethylamino]cyclopropyl}ethyl)-4,4-dimethyl-1,4-dihydrobenzo[d][1,3]oxazin-2-one

a)1-(2-{1-[2-(6-benzyloxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-2-hydroxyethylamino]cyclopropyl}ethyl)-4,4-dimethyl-1,4-dihydrobenzo[d][1,3]oxazin-2-one

Prepared from 900 mg (2.5 mmol) of6-benzyloxy-8-(2-ethoxy-2-hydroxyacetyl)-4H-benzo[1,4]oxazin-3-one and700 mg (2.7 mmol) of1-[2-(1-aminocyclopropyl)ethyl]-4,4-dimethyl-1,4-dihydrobenzo[d][1,3]oxazin-2-oneanalogously to the method described for Example 16a. White solid. Yield:630 mg (45%); mass spectroscopy: [M+H]⁺=558.

b)1-(2-{1-[2-hydroxy-2-(6-hydroxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)ethylamino]cyclopropyl}ethyl)-4,4-dimethyl-1,4-dihydrobenzo[d][1,3]oxazin-2-ol

590 mg (1.06 mmol) of1-(2-{1-[2-(6-benzyloxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-2-hydroxyethylamino]cyclopropyl}ethyl)-4,4-dimethyl-1,4-dihydrobenzo[d][1,3]oxazin-2-oneis dissolved in 30 mL of methanol and hydrogenated in the presence ofpalladium on charcoal (10%) at ambient temperature and 3 bar hydrogenpressure. Yield: 180 mg (36%); mass spectroscopy: [M+H]⁺=468.

The Examples listed below are obtained analogously to the methodsdescribed hereinbefore.

EXAMPLE 181-{3-[2-hydroxy-2-(6-hydroxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)ethylamino]-3-methylbutyl}spiro(cyclohexane-1,4′-2H-3′,1′-benzoxazin)-2′-one

EXAMPLE 191-{3-[2-hydroxy-2-(5-hydroxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)ethylamino]-3-methylbutyl}spiro(cyclohexane-1,4′-2H-3′,1′-benzoxazin)-2′-one

EXAMPLE 204,4-dimethyl-1-{3-[2-hydroxy-2-(6-hydroxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)ethylamino]propyl}-1,4-dihydrobenzo[d][1,3]oxazin-2-one

EXAMPLE 214,4-dimethyl-1-{3-[2-hydroxy-2-(5-hydroxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)ethylamino]propyl}-1,4-dihydrobenzo[d][1,3]oxazin-2-one

As has been found, the compounds of general formula 1 are characterizedby their range of uses in the therapeutic field. Particular mentionshould be made of those applications for which the compounds of formula1 according to the invention may preferably be used on the basis oftheir pharmaceutical activity as betamimetics.

These include, for example, the treatment of inflammatory andobstructive respiratory complaints, preferably the treatment of asthmaor COPD (chronic obstructive pulmonary disease), the inhibition ofpremature labor in midwifery (tocolysis), the restoration of the sinusrhythm in the heart in cases of atrio-ventricular block as well as thecorrecting of bradycardic heart rhythm disorders (antiarrhythmic agent),the treatment of circulatory shock (vasodilatation and increasing theheart-time volume) as well as the treatment of itching and skininflammation.

In one aspect the present invention relates to the use of the compoundsof formula 1 as pharmaceutical compositions. In another aspect thepresent invention relates to the use of the compounds of formula 1 forpreparing a pharmaceutical composition for the treatment of diseases,wherein therapeutically effective doses of a betamimetic can deliver atherapeutic benefit. It is particularly preferable to use compounds offormula 1 for preparing a pharmaceutical composition for the treatmentof inflammatory and obstructive respiratory complaints, particularlypreferably the treatment of asthma or COPD, for inhibiting prematurelabor in midwifery (tocolysis), for restoring the sinus rhythm in theheart in cases of atrio-ventricular block, for correcting bradycardicheart rhythm disorders, for treating circulatory shock (vasodilatationand increasing the heart-time volume) and for the treatment of itchingand skin inflammation. It is particularly preferred according to theinvention to use compounds of formula 1 for preparing a pharmaceuticalcomposition for the treatment of inflammatory and obstructiverespiratory complaints, particularly preferably for the treatment ofasthma or COPD. Also of particular importance is the use of compounds offormula 1 as described above for preparing a pharmaceutical compositionfor a once-a-day treatment of inflammatory and obstructive respiratorycomplaints, particularly preferably for a once-a-day treatment of asthmaor COPD.

Suitable preparations for administering the compounds of formula 1include for example tablets, capsules, suppositories, solutions,powders, etc. The content of the pharmaceutically active compound(s)should be in the range from 0.05 to 90 wt.-%, preferably 0.1 to 50 wt.-%of the composition as a whole. Suitable tablets may be obtained, forexample, by mixing the active substance(s) with known excipients, forexample inert diluents such as calcium carbonate, calcium phosphate orlactose, disintegrants such as corn starch or alginic acid, binders suchas starch or gelatine, lubricants such as magnesium stearate or talcand/or agents for delaying release, such as carboxymethyl cellulose,cellulose acetate phthalate, or polyvinyl acetate. The tablets may alsocomprise several layers.

Coated tablets may be prepared accordingly by coating cores producedanalogously to the tablets with substances normally used for tabletcoatings, for example collidone or shellac, gum arabic, talc, titaniumdioxide or sugar. To achieve delayed release or preventincompatibilities the core may also consist of a number of layers.Similarly the tablet coating may consist of a number of layers toachieve delayed release, possibly using the excipients mentioned abovefor the tablets.

Syrups or elixirs containing the active substances according to theinvention may additionally contain a sweetener such as saccharine,cyclamate, glycerol or sugar and a flavor enhancer, e.g., a flavoringsuch as vanillin or orange extract. They may also contain suspensionadjuvants or thickeners such as sodium carboxymethyl cellulose, wettingagents such as, for example, condensation products of fatty alcoholswith ethylene oxide, or preservatives such as p-hydroxybenzoates.

Solutions are prepared in the usual way, e.g., with the addition ofisotonic agents, preservatives such as p-hydroxybenzoates or stabilizerssuch as alkali metal salts of ethylenediaminetetraacetic acid,optionally using emulsifiers and/or dispersants, while if water is usedas diluent, for example, organic solvents may optionally be used assolubilizers or dissolving aids, and the solutions may be transferredinto injection vials or ampoules or infusion bottles.

Capsules containing one or more active substances may for example beprepared by mixing the active substances with inert carriers such aslactose or sorbitol and packing them into gelatine capsules.

Suitable suppositories may be made for example by mixing with carriersprovided for this purpose, such as neutral fats or polyethyleneglycol orthe derivatives thereof.

Excipients which may be used include, for example, water,pharmaceutically acceptable organic solvents such as paraffins (e.g.,petroleum fractions), vegetable oils (e.g., groundnut or sesame oil),mono- or polyfunctional alcohols (e.g., ethanol or glycerol), carrierssuch as, e.g., natural mineral powders (e.g., kaolins, clays, talc,chalk), synthetic mineral powders (e.g., highly dispersed silicic acidand silicates), sugars (e.g., cane sugar, lactose and glucose),emulsifiers (e.g., lignin, spent sulfite liquors, methylcellulose,starch and polyvinylpyrrolidone) and lubricants (e.g., magnesiumstearate, talc, stearic acid and sodium lauryl sulfate).

For oral use the tablets may obviously contain, in addition to thecarriers specified, additives such as sodium citrate, calcium carbonateand dicalcium phosphate together with various additional substances suchas starch, preferably potato starch, gelatine and the like. Lubricantssuch as magnesium stearate, sodium laurylsulfate and talc may also beused to produce the tablets. In the case of aqueous suspensions theactive substances may be combined with various flavor enhancers orcolorings in addition to the abovementioned excipients.

In the preferred use of the compounds of formula 1 for the treatment ofasthma or COPD according to the invention it is particularly preferredto use preparations or pharmaceutical formulations which are suitablefor inhalation. Inhalable preparations include inhalable powders,propellant-containing metered-dose aerosols or propellant-free inhalablesolutions Within the scope of the present invention, the termpropellant-free inhalable solutions also includes concentrates orsterile ready-to-use inhalable solutions. The formulations which may beused within the scope of the present invention are described in moredetail in the next part of the specification

The inhalable powders which may be used according to the invention maycontain 1 either on its own or in admixture with suitablephysiologically acceptable excipients. If the active substances 1 arepresent in admixture with physiologically acceptable excipients, thefollowing physiologically acceptable excipients may be used to preparethese inhalable powders according to the invention: monosaccharides(e.g., glucose or arabinose), disaccharides (e.g., lactose, saccharose,maltose), oligo- and polysaccharides (e.g., dextrans), polyalcohols(e.g., sorbitol, mannitol, xylitol), salts (e.g., sodium chloride,calcium carbonate) or mixtures of these excipients. Preferably, mono- ordisaccharides are used, while the use of lactose or glucose ispreferred, particularly, but not exclusively, in the form of theirhydrates. For the purposes of the invention, lactose is the particularlypreferred excipient, while lactose monohydrate is most particularlypreferred.

Within the scope of the inhalable powders according to the invention theexcipients have a maximum average particle size of up to 250 μm,preferably between 10 and 150 μm, most preferably between 15 and 80 μm.In some cases it may seem appropriate to add finer excipient fractionswith an average particle size of 1 to 9 μm to the excipient mentionedabove. These finer excipients are also selected from the group ofpossible excipients listed hereinbefore. Finally, in order to preparethe inhalable powders according to the invention, micronized activesubstance 1, preferably with an average particle size of 0.5 to 10 μm,more preferably from 1 to 5 μm, is added to the excipient mixture.Processes for producing the inhalable powders according to the inventionby grinding and micronizing and lastly mixing the ingredients togetherare known from the prior art. The inhalable powders according to theinvention may be administered using inhalers known from the prior art.

The inhalation aerosols containing propellant gas according to theinvention may contain the compounds 1 dissolved in the propellant gas orin dispersed form. The compounds 1 may be contained in separateformulations or in a common formulation, in which the compounds 1 areeither both dissolved, both dispersed or in each case only one componentis dissolved and the other is dispersed. The propellant gases which maybe used to prepare the inhalation aerosols are known from the prior art.Suitable propellant gases are selected from among hydrocarbons such asn-propane, n-butane or isobutane and halohydrocarbons such asfluorinated derivatives of methane, ethane, propane, butane,cyclopropane or cyclobutane. The abovementioned propellant gases may beused on their own or mixed together. Particularly preferred propellantgases are halogenated alkane derivatives selected from TG134a and TG227and mixtures thereof.

The propellant-driven inhalation aerosols may also contain otheringredients such as co-solvents, stabilizers, surfactants, antioxidants,lubricants and pH adjusters. All these ingredients are known in the art.

The propellant-driven inhalation aerosols according to the inventionmentioned above may be administered using inhalers known in the art(MDIs=metered dose inhalers).

Moreover, the active substances 1 according to the invention may beadministered in the form of propellant-free inhalable solutions andsuspensions. The solvent used may be an aqueous or alcoholic, preferablyan ethanolic solution. The solvent may be water on its own or a mixtureof water and ethanol. The relative proportion of ethanol compared withwater is not limited but the maximum is preferably up to 70 percent byvolume, more particularly up to 60 percent by volume and most preferablyup to 30 percent by volume. The remainder of the volume is made up ofwater. The solutions or suspensions containing 1 are adjusted to a pH of2 to 7, preferably 2 to 5, using suitable acids. The pH may be adjustedusing acids selected from inorganic or organic acids. Examples ofparticularly suitable inorganic acids include hydrochloric acid,hydrobromic acid, nitric acid, sulfuric acid and/or phosphoric acid.Examples of particularly suitable organic acids include ascorbic acid,citric acid, malic acid, tartaric acid, maleic acid, succinic acid,fumaric acid, acetic acid, formic acid and/or propionic acid etc.Preferred inorganic acids are hydrochloric and sulfuric acids. It isalso possible to use the acids which have already formed an acidaddition salt with one of the active substances. Of the organic acids,ascorbic acid, fumaric acid and citric acid are preferred. If desired,mixtures of the above acids may be used, particularly in the case ofacids which have other properties in addition to their acidifyingqualities, e.g., as flavorings, antioxidants or complexing agents, suchas citric acid or ascorbic acid, for example. According to theinvention, it is particularly preferred to use hydrochloric acid toadjust the pH.

If desired, the addition of edetic acid (EDTA) or one of the known saltsthereof, sodium edetate, as stabilizer or complexing agent may beomitted in these formulations. Other embodiments may contain thiscompound or these compounds. In a preferred embodiment the content basedon sodium edetate is less than 100 mg/100 ml, preferably less than 50mg/100 ml, more preferably less than 20 mg/100 ml. Generally, inhalablesolutions in which the content of sodium edetate is from 0 to 10 mg/100ml are preferred.

Co-solvents and/or other excipients may be added to the propellant-freeinhalable solutions. Preferred co-solvents are those which containhydroxyl groups or other polar groups, e.g., alcohols, particularlyisopropyl alcohol, glycols, particularly propyleneglycol,polyethyleneglycol, polypropylene glycol, glycol ether, glycerol,polyoxyethylene alcohols and polyoxyethylene fatty acid esters. Theterms excipients and additives in this context denote anypharmacologically acceptable substance which is not an active substancebut which can be formulated with the active substance or substances inthe physiologically suitable solvent in order to improve the qualitativeproperties of the active substance formulation. Preferably, thesesubstances have no pharmacological effect or, in connection with thedesired therapy, no appreciable or at least no undesirablepharmacological effect. The excipients and additives include, forexample, surfactants such as soya lecithin, oleic acid, sorbitan esters,such as polysorbates, polyvinylpyrrolidone, other stabilizers,complexing agents, antioxidants and/or preservatives which guarantee orprolong the shelf life of the finished pharmaceutical formulation,flavorings, vitamins and/or other additives known in the art. Theadditives also include pharmacologically acceptable salts such as sodiumchloride as isotonic agents.

The preferred excipients include antioxidants such as ascorbic acid, forexample, provided that it has not already been used to adjust the pH,vitamin A, vitamin E, tocopherols and similar vitamins and provitaminsoccurring in the human body.

Preservatives may be used to protect the formulation from contaminationwith pathogens. Suitable preservatives are those which are known in theart, particularly cetyl pyridinium chloride, benzalkonium chloride orbenzoic acid or benzoates such as sodium benzoate in the concentrationknown from the prior art. The preservatives mentioned above arepreferably present in concentrations of up to 50 mg/100 ml, morepreferably between 5 and 20 mg/100 ml.

Preferred formulations contain, in addition to the solvent water and theactive substance 1, only benzalkonium chloride and sodium edetate. Inanother preferred embodiment, no sodium edetate is present.

The dosage of the compounds according to the invention is naturallyhighly dependent on the method of administration and the complaint whichis being treated. When administered by inhalation the compounds offormula 1 are characterized by a high potency even at doses in the μgrange. The compounds of formula 1 may also be used effectively above theμg range. The dosage may then be in the milligram range, for example.

In another aspect the present invention relates to the abovementionedpharmaceutical formulations as such, which are characterized in thatthey contain a compound of formula 1, particularly preferably theabovementioned pharmaceutical formulations administered by inhalation.

The following examples of formulations illustrate the present inventionwithout restricting its scope:

Examples of Pharmaceutical Formulations

A) Tablets per tablet active substance of formula 1 100 mg lactose 140mg maize starch 240 mg polyvinylpyrrolidone  15 mg magnesium stearate  5mg 500 mg

The finely ground active substance, lactose and some of the corn starchare mixed together. The mixture is screened, then moistened with asolution of polyvinylpyrrolidone in water, kneaded, wet-granulated anddried. The granules, the remaining corn starch and the magnesiumstearate are screened and mixed together. The mixture is compressed toproduce tablets of suitable shape and size.

B) Tablets per tablet active substance of formula 1 80 mg lactose 55 mgmaize starch 190 mg  microcrystalline cellulose 35 mgpolyvinylpyrrolidone 15 mg sodium-carboxymethyl starch 23 mg magnesiumstearate  2 mg 400 mg 

The finely ground active substance, some of the corn starch, lactose,microcrystalline cellulose and polyvinylpyrrolidone are mixed together,the mixture is screened and worked with the remaining corn starch andwater to form a granulate which is dried and screened. The sodiumcarboxymethyl starch and the magnesium stearate are added and mixed inand the mixture is compressed to form tablets of a suitable size.

C) Ampoule solution active substance of formula 1 50 mg sodium chloride50 mg water for inj.  5 ml

The active substance is dissolved in water at its own pH or optionallyat pH 5.5 to 6.5 and sodium chloride is added to make it isotonic. Thesolution obtained is filtered free from pyrogens and the filtrate istransferred under aseptic conditions into ampoules which are thensterilized and sealed by fusion. The ampoules contain 5 mg, 25 mg and 50mg of active substance.

D) Metered-dose aerosol active substance of formula 1 0.005 sorbitolantrioleate 0.1  monofluorotrichloromethane and ad 100 TG134a:TG227 2:1

The suspension is transferred into a conventional aerosol container witha metering valve. Preferably, 50 μL of suspension are delivered perspray. The active substance may also be metered in higher doses ifdesired (e.g., 0.02% by weight).

F) Powder for inhalation active substance of formula 1 12 μg lactosemonohydrate ad 10 mg

The powder for inhalation is produced in the usual way by mixing theindividual ingredients together.

1. A pharmaceutical composition comprising a compound of formula 1′″

wherein: V is —CH₂—, —NH—, or —O—; R^(a) and R^(b) are eachindependently hydrogen, C₁₋₄-alkyl, or halogen-C₁₋₄-alkyl, or R^(a) andR^(b) together are a C₂₋₅-alkylene bridge wherein one or more hydrogenatoms are optionally replaced by halogen; R¹ and R^(1′) are eachindependently hydrogen, C₁₋₆-alkyl, C₃₋₆-cycloalkyl, halogen-C₁₋₆-alkyl,halogen-C₃₋₆-cycloalkyl, or C₁₋₆-alkylene-C₃₋₆-cycloalkyl, or R¹ andR^(1′) together are a C₂₋₅-alkylene bridge wherein one or more hydrogenatoms are optionally replaced by halogen; R², R^(2′), R^(2″), andR^(2′″) are each independently hydrogen, C₁₋₆-alkyl,halogen-C₁₋₆-alkylene, OH, HO—C₁₋₆-alkylene, —O—C₁₋₆-alkyl, C₆₋₁₀-aryl,C₆₋₁₀-aryl-C₁₋₄-alkylene, C₆₋₁₀-aryl-C₁₋₆-alkylene-O, COOH,COOC₁₋₆-alkyl, O—C₁₋₆-alkylene-COOH, O—C₁₋₆-alkylene-COOC₁₋₆-alkyl,NHSO₂—C₁₋₆-alkyl, CN, NH₂, NH—C₁₋₆-alkyl, N(C₁₋₆-alkyl)₂, NO₂,S—C₁₋₆-alkyl, SO₂—C₁₋₆-alkyl, SO—C₁₋₆-alkyl, O(CO)C₁₋₆-alkyl,COC₁₋₆-alkyl, NHCOC₁₋₆-alkyl, or halogen; and n is 0, 1, or 2, or anoptical isomer thereof, or a corresponding acid addition salt thereofwith a pharmacologically acceptable acid; and a pharmaceuticallyacceptable carrier or excipient thereof.
 2. The pharmaceuticalcomposition according to claim 1, wherein: V is —CH₂— or —O—; R^(a) andR^(b) are each independently hydrogen, C₁₋₄-alkyl, orhalogen-C₁₋₄-alkyl, or R^(a) and R^(b) together are a C₂₋₅-alkylenebridge wherein one or more hydrogen atoms are optionally replaced byhalogen; R¹ and R^(1′) are each independently hydrogen, methyl, ethyl,propyl, or cyclopropyl, or R¹ and R^(1′) together are —CH₂—CH₂,—CH₂—CH₂—CH₂—CH₂—, or —CH₂—CH₂—CH₂—CH₂—CH₂—; R² and R^(2′″) are eachhydrogen; and R^(2′) and R^(2″) are each independently hydrogen, methyl,CF₃, OH, methyloxy, benzyloxy, COOH, COOCH₃, or fluorine, or an opticalisomer thereof, or the corresponding acid addition salt thereof with apharmacologically acceptable acid.
 3. The pharmaceutical compositionaccording to claim 1 comprising two or more said compounds of formula1′″ and a pharmaceutically acceptable carrier or excipient thereof. 4.The pharmaceutical composition according to claim 1, wherein thepharmaceutical composition is administered by inhalation.
 5. Thepharmaceutical composition according to claim 4, which is in the form ofan inhalable powder, propellant-containing metered-dose aerosol orpropellant-free inhalable solution.
 6. A method of treating asthma orCOPD (chronic obstructive pulmonary disease) comprising administering toa patient in need thereof a therapeutically effective amount of apharmaceutical composition according to claim 1.